Grupos Investigadores

Líneas de Investigación

  • Combinaciones de anticuerpos monoclonales inmunoestimuladores.
  • Desarrollo de vacunas antitumorales.
  • Estrategias de inmunoterapia basadas en células NK.
  • Estrategias de inmunoterapia tumoral basadas en citoquinas.
  • Microscopia intravital.
  • Radioinmunoterapia.
  • Terapia celular adoptiva.
  • Tráfico leucocitario a través de los vasos linfáticos.

Palabras Clave

  • Anticuerpos
  • Citoquinas
  • Células dentríticas
  • Células NK
  • Integrinas
  • Leucocitos
  • Metástasis
  • Vacunas
  • Vasos linfáticos

Publicaciones Científicas desde 2018

  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Fernández de Sanmamed Gutiérrez, Miguel; Gonzalez Vaz, Javier; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.13 N° 3 2023 págs. 552 -569
    Resumen
    Twenty-five years ago, we reported that agonist anti-CD137 monoclonal antibodies eradicated transplanted mouse tumors because of enhanced CD8+ T-cell antitumor immunity. Mouse models indicated that anti-CD137 agonist antibodies synergized with various other therapies. In the clinic, the agonist antibody urelumab showed evidence for single-agent activity against melanoma and non-Hodgkin lymphoma but caused severe liver inflammation in a fraction of the patients. CD137's signaling domain is included in approved chimeric antigen receptors conferring persistence and efficacy. A new wave of CD137 agonists targeting tumors, mainly based on bispecific constructs, are in early-phase trials and are showing promising safety and clinical activity. Significance: CD137 (4-1BB) is a costimulatory receptor of T and natural killer lymphocytes whose activity can be exploited in cancer immunotherapy strategies as discovered 25 years ago. Following initial attempts that met unacceptable toxicity, new waves of constructs acting agonistically on CD137 are being developed in patients, offering signs of clinical and pharmacodynamic activity with tolerable safety profiles.
  • Autores: Araujo, D.; Greystoke, A.; Bates, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 1569-8041 Vol.34 N° 1 2023 págs. 48 - 60
    Resumen
    In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.
  • Autores: Suárez González, Lucia; Rodríguez Ruiz, María Esperanza; Rouzaut Subirá, Ana (Autor de correspondencia)
    Revista: CANCERS
    ISSN: 2072-6694 Vol.15 N° 1 2023 págs. 21
    Resumen
    Simple Summary The introduction of immunotherapy within the usual strategies for cancer treatment has meant an enormous advance in the survival of patients with very restrictive prognoses. However, a high percentage of patients still cannot benefit from it. The lack of response to immunotherapy is mainly due to resistance from the tumor stroma itself. The lymphatic endothelium constitutes a permeable vascular system from the stroma specially dedicated to balancing tissue homeostasis and leukocyte emigration. Most solid carcinomas present lymphatic microvasculature that participates in tumor progression ambivalently. On one hand, it facilitates the transit of immune cells toward the lymph nodes and therefore promotes the antitumor response; on the other hand, they constitute an accessible route through which tumor cells metastasize to the lymph nodes. Due to this double function, it is not easy to establish strategies that educate the lymphatic endothelium only in its antitumor function without compromising its participation in the immune response. In this review, we study how combinations of radiotherapy and immunotherapy can modulate lymphatic function to use them in therapeutic approaches. The study of lymphatic tumor vasculature has been gaining interest in the context of cancer immunotherapy. These vessels constitute conduits for immune cells' transit toward the lymph nodes, and they endow tumors with routes to metastasize to the lymph nodes and, from them, toward distant sites. In addition, this vasculature participates in the modulation of the immune response directly through the interaction with tumor-infiltrating leukocytes and indirectly through the secretion of cytokines and chemokines that attract leukocytes and tumor cells. Radiotherapy constitutes the therapeutic option for more than 50% of solid tumors. Besides impacting transformed cells, RT affects stromal cells such as endothelial and immune cells. Mature lymphatic endothelial cells are resistant to RT, but we do not know to what extent RT may affect tumor-aberrant lymphatics. RT compromises lymphatic integrity and functionality, and it is a risk factor to the onset of lymphedema, a condition characterized by deficient lymphatic drainage and compromised tissue homeostasis. This review aims to provide evidence of RT's effects on tumor vessels, particularly on lymphatic endothelial cell physiology and immune properties. We will also explore the therapeutic options available so far to modulate signaling through lymphatic endothelial cell receptors and their repercussions on tumor immune cells in the context of cancer. There is a need for careful consideration of the RT dosage to come to terms with the participation of the lymphatic vasculature in anti-tumor response. Here, we provide new approaches to enhance the contribution of the lymphatic endothelium to radioimmuno-oncology.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Penel, N.; Calvo, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.34 N° 5 2023 págs. 498 - 499
  • Autores: Gonzalez Vaz, Javier; Azpilicueta Lusarreta, Arantza; Ochoa Nieto, Maria del Carmen; et al.
    Revista: SCIENCE ADVANCES
    ISSN: 2375-2548 Vol.9 N° 33 2023 págs. eadf6692
    Resumen
    CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-?B and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137's cytoplasmic tail.
  • Autores: Mastelic-Gavillet, B.; Sarivalasis, A.; Lozano, L. E. ; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.14 N° 1119371 2023 págs. 1 - 12
    Resumen
    Background: The use of circulating cDC1 to generate anti-cancer vaccines is among the most promising approaches to overcome the limited immunogenicity and clinical efficacy of monocyte-derived DC. However, the recurrent lymphopenia and the reduction of DC numbers and functionality in patients with cancer may represent an important limitation of such approach. In patients with ovarian cancer (OvC) that had received chemotherapy, we previously showed that cDC1 frequency and function were reduced. Methods: We recruited healthy donors (HD, n=7) and patients with OvC at diagnosis and undergoing interval debulking surgery (IDS, n=6), primary debulking surgery (PDS, n=6) or at relapse (n=8). We characterized longitudinally phenotypic and functional properties of peripheral DC subsets by multiparametric flow cytometry. Results: We show that the frequency of cDC1 and the total CD141+ DC capacity to take up antigen are not reduced at the diagnosis, while their TLR3 responsiveness is partially impaired in comparison with HD. Chemotherapy causes cDC1 depletion and increase in cDC2 frequency, but mainly in patients belonging to the PDS group, while in the IDS group both total lymphocytes and cDC1 are preserved. The capacity of total CD141(+) DC and cDC2 to take up antigen is not impacted by chemotherapy, while the activation capacity upon Poly(I:C) (TLR3L) stimulation is further decreased. Conclusions: Our study provides new information about the impact of chemotherapy on the immune system of patients with OvC and sheds a new light on the importance of considering timing with respect to chemotherapy when designing new vaccination strategies that aim at withdrawing or targeting specific DC subsets.
  • Autores: Ochoa Nieto, Maria del Carmen; Sánchez-Gregorio, S.; De Andrea, Carlos Eduardo; et al.
    Revista: CELL REPORTS MEDICINE
    ISSN: 2666-3791 Vol.4 N° 4 2023 págs. 101009
    Resumen
    Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular car-cinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co -expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addi-tion of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 reg-imens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.
  • Autores: García-García, M. R. (Autor de correspondencia); Casares Lagar, Noelia; Martínez-Pérez, L. A.; et al.
    Revista: JOURNAL OF IMMUNOTOXICOLOGY
    ISSN: 1547-691X Vol.20 N° 1 2023 págs. 2175078
    Resumen
    Immunogenic cell death (ICD) is a form of cell death characterized by the release of danger signals required to trigger an adaptive immune response against tumor-associated antigens. Silver nanoparticles (AgNP) display anti-proliferative and cytotoxic effects in tumor cells, but it has not been previously studied whether AgNP act as an ICD inductor. The present study evaluated the in vitro release of calreticulin as a damage-associated molecular pattern (DAMP) associated with the cytotoxicity of AgNP and their in vivo anti-cancer effects. In vitro, mouse CT26 colon carcinoma and MCA205 fibrosarcoma cells were exposed to AgNP and then cell proliferation, adhesion, and release of calreticulin were determined. The results indicated there were time- and concentration-related anti-proliferative effects of AgNP in both the CT26 and MCA205 lines. Concurrently, changes in cell adhesion were detected mainly in the CT26 cells. Regarding DAMP detection, a significant increase in calreticulin was observed only in CT26 cells treated with doxorubicin and AgNP; however, no differences were found in the MCA205 cells. In vivo, the survival and growth of subcutaneous tumors were monitored after vaccination of mice with cell debris from tumor cells treated with AgNP or after intra-tumoral administration of AgNP to established tumors. Consequently, anti-tumoral prophylactic immunization with AgNP-dead cells failed to protect mice from tumor re-challenge; intra-tumor injection of AgNP did not induce a significant effect. In conclusion, there was a noticeable anti-tumoral effect of AgNP in vitro in both CT26 and MCA205 cell lines, accompanied by the release of calreticulin in CT26 cells. In vivo, immunization with cell debris derived from AgNP-treated tumor cells failed to induce a protective immune response in the cancer model mice. Clearly, further research is needed to determine if one could combine AgNP with other ICD inducers to improve the anti-tumor effect of these nanoparticles in vivo.
  • Autores: Olivera, I.; Bolaños Mateo, Elixabet; González Gomariz, José; et al.
    Revista: CELL REPORTS MEDICINE
    ISSN: 2666-3791 Vol.4 N° 3 2023 págs. 100978
    Resumen
    Interleukin-12 (IL-12) gene transfer enhances the therapeutic potency of adoptive T cell therapies. We previ-ously reported that transient engineering of tumor-specific CD8 T cells with IL-12 mRNA enhanced their sys-temic therapeutic efficacy when delivered intratumorally. Here, we mix T cells engineered with mRNAs to ex-press either single-chain IL-12 (scIL-12) or an IL-18 decoy-resistant variant (DRIL18) that is not functionally hampered by IL-18 binding protein (IL-18BP). These mRNA-engineered T cell mixtures are repeatedly in-jected into mouse tumors. Pmel-1 T cell receptor (TCR)-transgenic T cells electroporated with scIL-12 or DRIL18 mRNAs exert powerful therapeutic effects in local and distant melanoma lesions. These effects are associated with T cell metabolic fitness, enhanced miR-155 control on immunosuppressive target genes, enhanced expression of various cytokines, and changes in the glycosylation profile of surface proteins, enabling adhesiveness to E-selectin. Efficacy of this intratumoral immunotherapeutic strategy is recapitu-lated in cultures of tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells on IL -12 and DRIL18 mRNA electroporation.
  • Autores: Sandua Condado, Amaia; Fernández de Sanmamed Gutiérrez, Miguel; Rodríguez Ruiz, María Esperanza; et al.
    Revista: CLINICA CHIMICA ACTA
    ISSN: 0009-8981 Vol.543 2023 págs. 117303
    Resumen
    Aims: Characterization of PSA in extracellular microvesicles (EVs) and its reactivity to commercial methods. Materials and methods: EVs derived from serum of 47 prostate cancer (PCa) patients, 27 benign prostatic hyperplasia (BPH) patients and 42 healthy controls were analyzed. EVs isolation and quantification of PSA immunoreactive to total (ev-T-PSA) or free (ev-F-PSA) PSA immunoassays, were performed using commercial assays. PSA in CD81+ or CD63+ EVs was determined directly in serum by an immunocapture-ELISA (IC-ELISA). Results: Ev-T-PSA immunoreactive to Elecsys assay was detected in all samples. Median T-PSA ev/srm ratio was 2.20 % (Q1-Q3: 0.80-4.00 %), although in some samples this ratio reached 59 %. T-PSA ev/srm ratio was higher in those samples with serum T-PSA below 4 µg/L than in those exceeding that cut-off (p < 0.001). T-PSA ev/srm ratio was lower in PCa patients compared to healthy controls and BPH patients (p < 0.001). Elecsys immunoassays detected higher concentrations of ev-T-PSA and ev-F-PSA than Immulite (p < 0.001). PSA was detected by IC-ELISA more intensely in CD81+ EVs than in CD63+ EVs, and ev-T-PSA correlated with PSA+ CD63+ (p < 0.001) but not with PSA+ CD81+. Conclusion: EVs-bound PSA is another form of circulating PSA whose measurement could be easily performed in clinical laboratories by automated immunoassays.
  • Autores: Rodríguez Ruiz, María Esperanza; Serrano Mendioroz, Irantzu; Garate Soraluze, Eneko; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.11 N° 1 2023 págs. e005011
    Resumen
    BackgroundRadioimmunotherapy combines irradiation of tumor lesions with immunotherapy to achieve local and abscopal control of cancer. Most immunotherapy agents are given systemically, but strategies for delivering immunotherapy locally are under clinical scrutiny to maximize efficacy and avoid toxicity. Local immunotherapy, by injecting various pathogen-associated molecular patterns, has shown efficacy both preclinically and clinically. BO-112 is a viral mimetic based on nanoplexed double-stranded RNA (poly I:C) which exerts immune-mediated antitumor effects in mice and humans on intratumoral delivery. BO-112 and focal irradiation were used to make the proof-of-concept for local immunotherapy plus radiation therapy combinations.MethodsMurine transplantable tumor cell lines (TS/A, MC38 and B16-OVA) were used to show increased immunogenic features under irradiation, as well as in bilateral tumor models in which only one of the lesions was irradiated or/and injected with BO-112. Flow cytometry and multiplex tissue immunofluorescence were used to determine the effects on antitumor immunity. Depletions of immune cell populations and knockout mice for the IFNAR and BATF-3 genes were used to delineate the immune system requirements for efficacy.ResultsIn cultures of TS/A breast cancer cells, the combination of irradiation and BO-112 showed more prominent features of immunogenic tumor cell death in terms of calreticulin exposure. Injection of BO-112 into the tumor lesion receiving radiation achieved excellent control of the treated tumor and modest delays in contralateral tumor progression. Local effects were associated with more prominent infiltrates of antitumor cytotoxic tumor lymphocytes (CTLs). Importantly, local irradiation plus BO-112 in one of the tumor lesions that enhanced the therapeutic effects of radiotherapy on distant irradiated lesions that were not injected with BO-112. Hence, this beneficial effect of local irradiation plus BO-112 on a tumor lesion enhanced the therapeutic response to radiotherapy on distant non-injected lesions.ConclusionThis study demonstrates that local BO-112 immunotherapy and focal irradiation may act in synergy to achieve local tumor control. Irradiation plus BO-112 in one of the tumor lesions enhanced the therapeutic effects on distant irradiated lesions that were not injected with BO-112, suggesting strategies to treat oligometastatic patients with lesions susceptible to radiotherapy and with at least one tumor accessible for repeated BO-112 intratumoral injections.
  • Autores: Melero Bermejo, Ignacio; Tanos, T.; Bustamante, M.; et al.
    Revista: SCIENCE TRANSLATIONAL MEDICINE
    ISSN: 1946-6234 Vol.15 N° 695 2023 págs. abp9229
    Resumen
    This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein alpha (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent (n = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks (n = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8+ and Ki67+CD8+T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
  • Autores: Ascierto, P. A. (Autor de correspondencia); Mandala, M.; Ferrucci, P. F.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.41 N° 2 2023 págs. 212 - 221
    Resumen
    PURPOSE Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600-mutant metastatic melanoma.METHODS SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447). Patients with untreated, metastatic BRAFV600-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks x four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication.RESULTS A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of # 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged.CONCLUSION Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600-mutant melanoma.
  • Autores: Cirella, Assunta; Bolaños Mateo, Elixabet; Luri Rey, Carlos; et al.
    Revista: MOLECULAR THERAPY - NUCLEIC ACIDS
    ISSN: 2162-2531 Vol.33 2023 págs. 668 - 682
    Resumen
    Intratumoral immunotherapy strategies for cancer based on interleukin-12 (IL-12)-encoding cDNA and mRNA are under clinical development in combination with anti-PD-(L)1 monoclonal antibodies. To make the most of these approaches, we have constructed chimeric mRNAs encoding single-chain IL-12 fused to single-chain fragment variable (scFv) antibodies that bind to transforming growth factor b (TGF-b) and CD137 (4-1BB). Several neutralizing TGF- b agents and CD137 agonists are also undergoing early-phase clinical trials. To attain TGF-beta and CD137 binding by the constructions, we used bispecific tandem scFv antibodies (taFvs) derived from the specific 1D11 and 1D8 monoclonal antibodies (mAbs), respectively. Transfection of mRNAs encoding the chimeric constructs achieved functional expression of the proteins able to act on their targets. Upon mRNA intratumoral injections in the transplantable mouse cancer models CT26, MC38, and B16OVA, potent therapeutic effects were observed following repeated injections into the tumors. Efficacy was dependent on the number of CD8+ T cells able to recognize tumor antigens that infiltrated the malignant tissue. Although the abscopal effects on concomitant uninjected lesions were modest, such distant effects on untreated lesions were markedly increased when combined with systemic PD-1 blockade.
  • Autores: Di Trani, Claudia Augusta; Cirella, A.; Arrizabalaga Astigarraga, Leire; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.12 N° 1 2023 págs. 2147317
    Resumen
    Previous studies have shown that local delivery of tumor antigen-specific CD8(+) T lymphocytes engineered to transiently express single-chain IL-12 mRNA is highly efficacious. Peritoneal dissemination of cancer is a frequent and often fatal patient condition usually diagnosed when the tumor burden is too large and hence uncontrollable with current treatment options. In this study, we have modeled intracavitary adoptive T cell therapy with OVA-specific OT-I T cells electroporated with IL-12 mRNA to treat B16-OVA and PANC02-OVA tumor spread in the peritoneal cavity. Tumor localization in the omentum and the effects of local T-cell encounter with the tumor antigens were monitored, the gene expression profile evaluated, and the phenotypic reprogramming of several immune subsets was characterized. Intraperitoneal administration of T cells promoted homing to the omentum more effectively than intravenous administration. Transient IL-12 expression was responsible for a favorable reprogramming of the tumor immune microenvironment, longer persistence of transferred T lymphocytes in vivo, and the development of immunity to endogenous antigens following primary tumor eradication. The efficacy of the strategy was at least in part recapitulated with the adoptive transfer of lower affinity transgenic TCR-bearing PMEL-1 T lymphocytes to treat the aggressive intraperitoneally disseminated B16-F10 tumor. Locoregional adoptive transfer of transiently IL-12-armored T cells appears to offer promising therapeutic advantages in terms of anti-tumor efficacy to treat peritoneal carcinomatosis.
  • Autores: Alsina, M.; Ponz-Sarvise, M. ; Lopez Garcia, D. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.34 2023 págs. S2 - S3
  • Autores: Di Trani, C. A.; Fernández Fernández, Myriam; Cirella, A.; et al.
    Revista: EXPERT OPINION ON DRUG DISCOVERY
    ISSN: 1746-0441 Vol.17 N° 1 2022 págs. 41 - 53
    Resumen
    Introduction Immune checkpoint inhibitors and adoptive T-cell therapy based on chimeric antigen receptors are the spearhead strategies to exploit the immune system to fight cancer. To take advantage of the full potential of the immune system, cancer immunotherapy must incorporate new biotechnologies such as mRNA technology that may synergize with already approved immunotherapies and act more effectively on immune targets. Areas covered This review describes the basics of mRNA biotechnology and provides insight into the recent advances in the use of mRNA for the local and systemic delivery of immunostimulatory antibodies, proinflammatory cytokines or for optimizing adoptive T-cell therapy. Expert opinion mRNA-based nanomedicines have great potential to expand the arsenal of immunotherapy tools due to their ability to simplify and accelerate drug development and their suitability for transient and local expression of immunostimulatory molecules, whose systemic and sustained expression would be toxic. The success of mRNA-based COVID-19 vaccines has highlighted the feasibility of this approach. Continuous advances in the delivery and construction of RNA-based vectors hold promise for improvements in clinical efficacy.
  • Autores: Segués, A.; Huang, S.; Sijts, A.; et al.
    Revista: International review of cell and molecular biology
    ISSN: 1937-6448 Vol.369 2022 págs. 45 - 70
    Resumen
    The recent clinical approval of different Bi-specific antibodies (BsAbs) has revealed the great therapeutic potential of this novel class of biologicals. For example, the bispecific T-cell engager (BiTE), Blinatumomab, demonstrated the unique capacity of BsAbs to link T-cells with tumor cells, inducing targeted tumor cell removal. Additionally, Amivantamab, recognizing the EGFR and cMet in cis, revealed a substantial improvement of therapeutic efficacy by concomitantly targeting two tumor antigens. Cis-targeting BsAbs furthermore allow discerning cell populations which concurrently express two antigens, for which each antigen expression pattern in itself might not be selective. In this way, BsAbs harbor the great prospect of being more specific and showing fewer side effects than monoclonal antibodies. Nevertheless, BsAbs have also faced major obstacles, for instance, in ensuring reliable assembly and clinical-grade purification. In this review, we summarize the different available antibody platforms currently used for the generation of IgG-like and non-IgG-like BsAbs and explain which approaches have been used to assemble those BsAbs which are currently approved for clinical application. By focusing on the example of regulatory T-cells (Tregs) and the different, ongoing approaches to develop BsAbs specifically targeting Tregs within the tumor microenvironment, our review highlights the huge potential as well as the pitfalls BsAb face in order to emerge as one of the most effective therapeutic biologicals targeting desired cell populations in a highly selective way. Such BsAb may improve treatment efficacy and reduce side effects, thereby opening novel treatment opportunities for a range of different diseases, such as cancer or autoimmune diseases.
  • Autores: Dunai, C.; Ames, E.; Ochoa Nieto, Maria del Carmen; et al.
    Revista: INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY
    ISSN: 1937-6448 Vol.370 2022 págs. 65 - 122
    Resumen
    Natural killer (NK) cells are innate lymphocytes that control tumor progression by not only directly killing cancer cells, but also by regulating other immune cells, helping to orchestrate a coordinated anti-tumor response. However, despite the tremendous potential that this cell type has, the clinical results obtained from diverse NK cell-based immunotherapeutic strategies have been, until recent years, rather modest. The intrinsic regulatory mechanisms that are involved in the control of their activation as well as the multiple mechanisms that tumor cells have developed to escape NK cell-mediated cytotoxicity likely account for the unsatisfactory clinical outcomes. The current approaches to improve long-term NK cell function are centered on modulating different molecules involved in both the activation and inhibition of NK cells, and the latest data seems to advocate for combining strategies that target multiple aspects of NK cell regulation. In this review, we summarize the different strategies (such as engineered NK cells, CAR-NK, NK cell immune engagers) that are currently being used to take advantage of this potent and complex immune cell.
  • Autores: Cirella, A.; Luri Rey, Carlos; Di Trani, Claudia Augusta; et al.
    Revista: PHARMACOLOGY AND THERAPEUTICS
    ISSN: 0163-7258 Vol.239 2022 págs. 108189
    Resumen
    Interleukin-12 is considered a potent agent to enhance antitumor immune responses. It belongs to a family of heterodimeric cytokines with key roles in the up-regulation and down-regulation of cellular immunity. Since its discovery, recombinant IL-12 was found to exert potent antitumor effects in rodent tumor models and was rapidly tested in the clinic with an unfavorable benefit/toxicity profile. Localized delivery of IL-12 dramatically improves the therapeutic index and this approach is being applied in the clinic based on in-vivo electroporation of naked plasmid DNA encoding IL-12, mRNA formulations, viral vectors and tumor-targeted fusion proteins. Other biotechnology strategies such as IL-12-engineered local adoptive cell therapy and pro-cytokines can also be used to improve results and broaden the therapeutic window. Combination strategies of such localized IL-12-based approaches with checkpoint inhibitors are yielding promising results both preclinically and in the early-phase clinical trials.
  • Autores: Di Trani, Claudia Augusta; Cirella, A.; Arrizabalaga Astigarraga, Leire; et al.
    Revista: International review of cell and molecular biology
    ISSN: 1937-6448 Vol.369 2022 págs. 107 - 141
    Resumen
    Cytokines are pleiotropic soluble proteins used by immune cells to orchestrate a coordinated response against pathogens and malignancies. In cancer immunotherapy, cytokine-based drugs can be developed potentiating pro-inflammatory cytokines or blocking immunosuppressive cytokines. However, the complexity of the mechanisms of action of cytokines requires the use of biotechnological strategies to minimize systemic toxicity, while potentiating the antitumor response. Sequence mutagenesis, fusion proteins and gene therapy strategies are employed to enhance the half-life in circulation, target the desired bioactivity to the tumor microenvironment, and to optimize the therapeutic window of cytokines. In this review, we provide an overview of the different strategies currently being pursued in pre-clinical and clinical studies to make the most of cytokines for cancer immunotherapy.
  • Autores: Mendoza-Valderrey, A.; Alvarez Rodriguez, Maite; De Maria, A.; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.11 N° 19 2022 págs. 3147-*
    Resumen
    In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.
  • Autores: Lin, M. J.; Svensson-Arvelund, J.; Lubitz, G. S.; et al.
    Revista: NATURE CANCER
    ISSN: 2662-1347 Vol.3 N° 8 2022 págs. 911 - 926
    Resumen
    Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic. After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
  • Autores: Fernández de Sanmamed Gutiérrez, Miguel; Berraondo López, Pedro; Rodríguez Ruiz, María Esperanza; et al.
    Revista: NATURE CANCER
    ISSN: 2662-1347 Vol.3 N° 6 2022 págs. 665 - 680
    Resumen
    Checkpoint inhibitor-based cancer immunotherapy is often combined in the clinic with other immunotherapy strategies, targeted therapies, chemotherapy or standard-of-care treatments to achieve superior therapeutic efficacy. The large number of immunotherapy combinations that are currently undergoing clinical testing necessitate the establishment of faithful criteria to prioritize optimal combinations with evidence of synergy, to determine their safety and optimal sequence of administration and to identify biomarkers of therapy resistance and response. In this review, we focus on recent developments in immunotherapy combinations and reflect on how combinations should be optimized to maximize the impact of immunotherapy in clinical oncology.
  • Autores: Aranda Vega, Fernando; Eguren Santamaría, Iñaki; Bella Carreño, Ángela; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.28 N° 10 2022 págs. 1993 - 1995
    Resumen
    Ovarian cancer is often limited to the peritoneal cavity in the form of peritoneal carcinomatosis. Peritoneal spreading offers the opportunity for locoregional delivery of combinations of immuno- therapy agents, maximizing bioavailability while potentially reduc-ing systemic exposure and side effects.
  • Autores: Berraondo López, Pedro; Sullivan, R. J. (Autor de correspondencia)
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 9 2022 págs. 855 - 856
  • Autores: Wang, J. (Autor de correspondencia); Johnston, B. (Autor de correspondencia); Berraondo López, Pedro
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.13 2022 págs. 985326
  • Autores: Gómez-Roca, C. (Autor de correspondencia); Cassier, P.; Zamarin, D.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 5 2022 págs. e004076
    Resumen
    Background This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naive or experienced for immune checkpoint blockers (ICBs). Methods Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. Results Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade >= 3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naive UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naive UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naive patients. Conclusion Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
  • Autores: Bella Carreño, Ángela; Arrizabalaga Astigarraga, Leire; Di Trani, Claudia Augusta; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.11 N° 1 2022 págs. 2098657
    Resumen
    Recombinant-modified vaccinia virus Ankara (rMVA) is known to elicit potent antitumor immune responses in preclinical models due to its inherent ability to activate the innate immune system and the activation of adaptive responses mediated by the expression of tumor antigens and costimulus-providing molecules, such as CD40L and CD137L. Here, we evaluated different rMVA vectors in preclinical peritoneal carcinomatosis models (ID8.OVA-Vegf/GFP and MC38). We compared rMVA vectors expressing a tumor antigen (OVA or gp70) either alone or co-expressed with CD40L or/and CD137L. In tumor-free mice, the vector coding for the triple combination was only slightly superior, whereas, in tumor-bearing animals, we observed a synergistic induction of T lymphocytes specific against vector-encoded and non-encoded tumor-associated antigens. The enhanced activation of the immune response was associated with improved survival in mice with peritoneal carcinomatosis treated with a rMVA vector encoding both CD40L and CD137L. Thus, the triple transgene combination in vaccinia viral vectors represents a promising strategy for the treatment of peritoneal carcinomatosis.
  • Autores: Bella Carreño, Ángela (Autor de correspondencia); Arrizabalaga Astigarraga, Leire; Di Trani, Claudia Augusta; et al.
    Revista: INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY
    ISSN: 1937-6448 Vol.371 2022 págs. 117 - 131
    Resumen
    Ovarian cancer often spreads out of the ovary before a patient is diagnosed and is the deadliest gynecological malignancy. The aggressiveness of ovarian cancer is determined by the progression in the form of peritoneal carcinomatosis, a stage with a poor prognosis and an untreatable condition in most patients. One of the first tumor nests or the origin of metastasis in the peritoneal cavity is the omentum. The omentum contains immune aggregates, called milky spots, embedded in adipose tissue, which support tumor growth by various mechanisms, including immunosuppressive immune cells and metabolic functions. In this sense, the abundance of blood vessels, omental resident macrophages, and chemokines, among other factors, are known to promote invasiveness, proliferation and resistance to cancer therapies. As a result, surgical practice employed in advanced-stage ovarian cancer almost constantly includes omentectomy. Paradoxically, the omentum is considered the abdominal policeman that contributes to peritoneal immunity by capturing antigens and pathogens from the peritoneal cavity and promoting effective immune responses against microbes. Why immunosurveillance against the metastatic tumor does not take place in the omentum? Could omental immune responses be activated with immunotherapeutic interventions? The omentum has largely been ignored in cancer immunology and immunotherapy, and the potential translational implications of this in ovarian cancer are still unclear. Here, we focus on the dual role of the omentum in ovarian cancer: its role in antitumor immune responses versus its activities fostering cancer progression. Copyright © 2022 Elsevier Inc. All rights reserved.
  • Autores: Palomero, J.; Panisello, C.; Lozano-Rabella, M.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 12 2022 págs. e005443
    Resumen
    BackgroundDespite the growing interest in immunotherapeutic interventions for endometrial cancer (EC), the prevalence, phenotype, specificity and prognostic value of tumor infiltrating lymphocytes (TILs) in this tumor type remains unclear.MethodsTo better understand the role of TILs in EC, we analyzed the phenotypic traits of CD8(+) and CD4(+) EC(-)resident T cells from 47 primary tumors by high-dimensional flow cytometry. In addition, CD8(+) and CD4(+) TIL subpopulations were isolated based on the differential expression of programmed cell death protein-1 (PD-1) (negative, dim and high) and CD39 (positive or negative) by fluorescence activated cell sorting (FACS), expanded in vitro, and screened for autologous tumor recognition. We further investigated whether phenotypic markers preferentially expressed on CD8(+) and CD4(+) tumor-reactive TIL subsets were associated with the four distinct molecular subtypes of EC, tumor mutational burden and patient survival.ResultsWe found that CD8(+)TILs expressing high levels of PD-1 (PD-1hi) co-expressed CD39, TIM-3, HLA-DR and CXCL13, as compared with TILs lacking or displaying intermediate levels of PD-1 expression (PD-1(-) and PD-1(dim), respectively). Autologous tumor reactivity of sorted and in vitro expanded CD8+ TILs demonstrated that the CD8(+)PD-1(dim)CD39(+) and PD-1(hi)CD39(+) T cell subsets both contained tumor-reactive TILs and that a higher level of PD-1 expression was associated with increased CD39 and a superior frequency of tumor reactivity. With respect to CD4(+) T conventional (Tconv) TILs, co-expression of inhibitory and activation markers was more apparent on PD-1(hi) compared with PD-1(-) or PD-1(dim) T cells, and in fact, it was the CD4(+)PD-1(hi) subpopulation that accumulated the antitumor T cells irrespective of CD39 expression. Most importantly, detection of CD8(+)PD-1(hi)CD39+ and CD4(+)PD-1(hi) tumor-reactive T-cell subsets, but also markers specifically expressed by these subpopulations of TILs, that is, PD-1(hi), CD39, CXCL13 and CD103 by CD8(+) TILs and PD-1(hi) and CXCL13 by CD4(+) Tconv TILs, correlated with prolonged survival of patients with EC.ConclusionsOur results demonstrate that EC are frequently infiltrated by tumor-reactive TILs, and that expression of PD-1(hi) and CD39 or PD-1(hi) can be used to select and expand CD8(+) and CD4(+) tumor-reactive TILs, respectively. In addition, biomarkers preferentially expressed on tumor-reactive TILs, rather than the frequency of CD3(+), CD8(+) and CD4(+) lymphocytes, hold prognostic value suggesting their protective role in antitumor immunity.
  • Autores: Sonzini, G.; Granados-Aparici, S.; Sanegre, S.; et al.
    Revista: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN: 2296-634X Vol.10 2022 págs. 1052098
    Resumen
    The incidence of new cancer cases is expected to increase significantly in the future, posing a worldwide problem. In this regard, precision oncology and its diagnostic tools are essential for developing personalized cancer treatments. Digital pathology (DP) is a particularly key strategy to study the interactions of tumor cells and the tumor microenvironment (TME), which play a crucial role in tumor initiation, progression and metastasis. The purpose of this study was to integrate data on the digital patterns of reticulin fiber scaffolding and the immune cell infiltrate, transcriptomic and epigenetic profiles in aggressive uterine adenocarcinoma (uADC), uterine leiomyosarcoma (uLMS) and their respective lung metastases, with the aim of obtaining key TME biomarkers that can help improve metastatic prediction and shed light on potential therapeutic targets. Automatized algorithms were used to analyze reticulin fiber architecture and immune infiltration in colocalized regions of interest (ROIs) of 133 invasive tumor front (ITF), 89 tumor niches and 70 target tissues in a total of six paired samples of uADC and nine of uLMS. Microdissected tissue from the ITF was employed for transcriptomic and epigenetic studies in primary and metastatic tumors. Reticulin fiber scaffolding was characterized by a large and loose reticular fiber network in uADC, while dense bundles were found in uLMS. Notably, more similarities between reticulin fibers were observed in paired uLMS then paired uADCs. Transcriptomic and multiplex immunofluorescence-based immune profiling showed a higher abundance of T and B cells in primary tumor and in metastatic uADC than uLMS. Moreover, the epigenetic signature of paired samples in uADCs showed more differences than paired samples in uLMS. Some epigenetic variation was also found between the ITF of metastatic uADC and uLMS. Altogether, our data suggest a correlation between morphological and molecular changes at the ITF and the degree of aggressiveness. The use of DP tools for characterizing reticulin scaffolding and immune cell infiltration at the ITF in paired samples together with information provided by omics analyses in a large cohort will hopefully help validate novel biomarkers of tumor aggressiveness, develop new drugs and improve patient quality of life in a much more efficient way.
  • Autores: Tabernero, J. (Autor de correspondencia); Andre, F.; Blay, J. Y.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.7 N° 2 2022 págs. 100419
    Resumen
    Background: The programmed death-ligand 1 inhibitor atezolizumab had shown clinical activity against several advanced malignancies. Patients and methods: This phase II, open-label basket study (NCT02458638) was conducted in 16 main cohorts of patients aged >= 18 years with stage III or IV solid tumors. In stage I, 12 patients were enrolled into each cohort. Treatment was atezolizumab 1200 mg intravenously every 3 weeks until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was the non-progression rate (NPR) at 18 weeks in treated, assessable patients. NPR <= 20% was not of interest for development as monotherapy, and NPR >= 0% was defined as the threshold of benefit/success. If >= 3 patients had non-progressive disease in stage I (interim analysis), 13 additional patients could be enrolled into stage II (final analysis). Secondary efficacy and safety endpoints were also evaluated. Results: Overall, 474 patients were enrolled and treated; 433 were included in the efficacy set. Due partly to slow recruitment because of competing trials and limited efficacy at interim analyses, enrollment was stopped early, including in cohorts that passed stage I boundaries of success. NPR was >20% in five cohorts: cervical cancer {n = 27; NPR 44.4% [95% confidence interval (CI) 25.5% to 64.7%]}; follicular/papillary thyroid cancer [n = 11; 54.5% (95% CI 23.4% to 83.3%)]; thymoma [n = 13; 76.9% (95% CI: 46.2% to 95.0%)]; gastroenteropancreatic (GEP) and lung neuroendocrine tumors [NETs; n = 24; 41.7% (95% CI 22.1% to 63.4%)], and low/intermediate grade carcinoid GEP and lung NETs [n = 12; 58.3% (95% CI 27.7% to 84.8%)]. Treatment-related adverse events occurred in 55.3% of patients overall, and at grade 3, 4, and 5 in 10.3%, 1.7%, and 0.4%, respectively. Conclusions: Atezolizumab monotherapy was effective in the cervical cancer cohort. The interim benefit threshold was crossed in patients with follicular/papillary thyroid cancer, thymoma, and GEP and lung NETs, but recruitment was stopped before these signals could be confirmed in stage II. Safety was consistent with previous findings.
  • Autores: Teijeira Sánchez, Álvaro (Autor de correspondencia); Miguéliz Basterra, Itziar; Garasa, S.; et al.
    Revista: THERANOSTICS
    ISSN: 1838-7640 Vol.12 N° 3 2022 págs. 1373 - 1387
    Resumen
    Rationale: The CEA-CD3 T cell bispecific antibody cibisatamab (CEA-TCB) is currently undergoing clinical trials. Here we study its performance against three-dimensional tumor organoids in cocultures with T cells as compared to a higher affinity CEACAM5-CD3 (CEACAM5-TCB) bispecific antibody using time-lapse confocal microscopy. Methods: Pre-labelled spheroids derived from colon cancer cell lines and primary organoids derived from four colorectal cancer surgical specimens, which expressed different graded levels of CEA, were exposed in cocultures to T lymphocytes. Cocultures were treated with CEA-CD3 T-cell engagers and were followed by live confocal microscopy. Caspase 3 activation detected in real-time was used as an indicator of tumor cell death. Co-cultures were also set up with autologous tumor-associated fibroblasts to test the co-stimulatory effect of a fibroblast activated protein (FAP)- targeted 4-1BBL bispecific antibody fusion protein currently undergoing clinical trials. Results: Tumor-cell killing of 3D colon carcinoma cultures was dependent on the levels of surface CEA expression, in such a way that the lower affinity agent (CEA-TCB) did not mediate killing by human preactivated T cells below a certain CEA expression threshold, while the high affinity construct (CEACAM5-TCB) remained active on the low CEA expressing organoids. Modelling heterogeneity in the levels of CEA expression by coculturing CEA high and low organoids showed measurable but weak bystander killing. Cocultures of tumor organoids, autologous fibroblasts and T cells allowed to observe a costimulatory effect of anti-FAP-4-1BBL both to release IFN gamma and to attain more efficacious tumor cell killing. Conclusion: Three-dimensional tumor cocultures with T cells using live confocal microscopy provide suitable models to test the requirements for colon-cancer redirected killing as elicited by CEA-targeted T-cell engagers undergoing clinical trials and treatment allow combinations to be tested in a relevant preclinical system.
  • Autores: López Janeiro, Álvaro; Villalba Esparza, María; Emilia-Brizzi, M; et al.
    Revista: JOURNAL OF PATHOLOGY
    ISSN: 0022-3417 Vol.258 N° 4 2022 págs. 426 - 436
    Resumen
    Endometrial tumors show substantial heterogeneity in their immune microenvironment. This heterogeneity could be used to improve the accuracy of current outcome prediction tools. We assessed the immune microenvironment of 235 patients diagnosed with low-grade, early-stage endometrial cancer. Multiplex quantitative immunofluorescence was carried out to measure CD8, CD68, FOXP3, PD-1, and PD-L1 markers, as well as cytokeratin (CK), on tissue microarrays. Clustering results revealed five robust immune response patterns, each associated with specific immune populations, cell phenotypes, and cell spatial clustering. Most samples (69%) belonged to the immune-desert subtype, characterized by low immune cell densities. Tumor-infiltrating lymphocyte (TIL)-rich samples (4%) displayed high CD8(+) T-cell infiltration, as well as a high percentage of CD8/PD-1(+) cells. Immune-exclusion samples (19%) displayed the lowest CD8(+) infiltration combined with high PD-L1 expression levels in CK+ tumor cells. In addition, they demonstrated high tumor cell spatial clustering as well as increased spatial proximity of CD8(+)/PD-1(+) and CK/PD-L1(+) cells. FOXP3 and macrophage-rich phenotypes (3% and 4% of total samples) displayed relatively high levels of FOXP3(+) regulatory T-cells and CD68(+) macrophages, respectively. These phenotypes correlated with clinical outcomes, with immune-exclusion tumors showing an association with tumor relapse. When compared with prediction models built using routine pathological variables, models optimized with immune variables showed increased outcome prediction capacity (AUC = 0.89 versus 0.78) and stratification potential. The improved prediction capacity was independent of mismatch repair protein status and adjuvant radiotherapy treatment. Further, immunofluorescence results could be partially recapitulated using single-marker immunohistochemistry (IHC) performed on whole tissue sections. TIL-rich tumors demonstrated increased CD8(+) T-cells by IHC, while immune-exclusion tumors displayed a lack of CD8(+) T-cells and frequent expression of PD-L1 in tumor cells. Our results demonstrate the capability of the immune microenvironment to improve standard prediction tools in low-grade, early-stage endometrial carcinomas.
  • Autores: Fizazi, K. (Autor de correspondencia); Retz, M.; Petrylak, D. P.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 8 2022 págs. e004761
    Resumen
    Background CheckMate 9KD (NCT03338790) is a nonrandomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib. Methods CheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0-1. Cohort A1 included patients with postchemotherapy mCRPC (1-2 prior taxane-based regimens) and <= 2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naive mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing <= 2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA(50)-RR; >= 50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results Outcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9-21.2) (n=58), 17.2% (5.8-35.8) (n=29), and 33.3% (7.5-70.1) (n=9); confirmed PSA(50)-RR: 11.9% (5.9-20.8) (n=84), 18.2% (8.2-32.7) (n=44), and 41.7% (15.2-72.3) (n=12); median rPFS: 4.9 (3.7-5.7) (n=88), 5.8 (3.7-8.4) (n=45), and 5.6 (2.8-15.7) (n=12) months; and median OS: 13.9 (10.4-15.8) (n=88), 15.4 (11.4-18.2) (n=45), and 15.2 (3.0-not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9-30.5) (n=39), 25.0% (8.7-49.1) (n=20), and 33.3% (7.5-70.1) (n=9); confirmed PSA(50)-RR: 27.3% (17.0-39.6) (n=66), 41.9 (24.5-60.9) (n=31), and 84.6% (54.6-98.1) (n=13); median rPFS: 8.1 (5.6-10.9) (n=71), 10.9 (6.7-12.0) (n=34), and 10.9 (5.6-12.0) (n=15) months; and median OS: 20.2 (14.1-22.8) (n=71), 22.7 (14.1-not estimable) (n=34), and 20.2 (11.1-not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3-4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively. Conclusions Nivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naive mCRPC, particularly those harboring BACA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial.
  • Autores: Muik, A.; Garralda, E.; Altintas, I.; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.12 N° 5 2022 págs. 1248 - 1265
    Resumen
    Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell-mediated antitumor immunity. DuoBody-PD-L1x4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-inhuman study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy. SIGNIFICANCE: DuoBody-PD-L1x4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs.
  • Autores: Vukovic, N.; Halabi, S.; Russo-Cabrera, J.S.; et al.
    Revista: JBC PAPERS IN PRESS
    ISSN: 1083-351X Vol.298 N° 8 2022 págs. 102153
    Resumen
    The generation of bispecific antibodies (bsAbs) targeting two different antigens opens a new level of specificity and, compared to mAbs, improved clinical efficacy in cancer therapy. Currently, the different strategies for development of bsAbs primarily focus on IgG isotypes. Nevertheless, in comparison to IgG isotypes, IgE has been shown to offer superior tumor control in preclinical models. Therefore, in order to combine the promising potential of IgE molecules with increased target selectivity of bsAbs, we developed dual tumor-associated antigen-targeting bispecific human IgE antibodies. As proof of principle, we used two different pairing approaches - knobs-into-holes and leucine zipper-mediated pairing. Our data show that both strategies were highly efficient in driving bispecific IgE formation, with no undesired pairings observed. Bispecific IgE antibodies also showed a dose-dependent binding to their target antigens, and cell bridging experiments demonstrated simultaneous binding of two different antigens. As antibodies mediate a major part of their effector functions through interaction with Fc receptors (FcRs) expressed on immune cells, we confirmed FcepsilonR binding by inducing invitro mast cell degranulation and demonstrating invitro and invivo monocyte-mediated cytotoxicity against target antigen-expressing Chinese hamster ovary cells. Moreover, we demonstrated that the IgE bsAb construct was significantly more efficient in mediating antibody-dependent cell toxicity than its IgG1 counterpart. In conclusion, we describe the successful development of first bispecific IgE antibodies with superior antibody-dependent cell toxicity-mediated cell killing in comparison to IgG bispecific antibodies. These findings highlight the relevance of IgE-based bispecific antibodies for clinical application.
  • Autores: Kowalska, D.; Kuzniewska, A.; Senent, Y.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.13 2022 págs. 946522
    Resumen
    Numerous publications have underlined the link between complement C5a and the clinical course of COVID-19. We previously reported that levels of C5a remain high in the group of severely ill patients up to 90 days after hospital discharge. We have now evaluated which complement pathway fuels the elevated levels of C5a during hospitalization and follow-up. The alternative pathway (AP) activation marker C3bBbP and the soluble fraction of C4d, a footprint of the classical/lectin (CP/LP) pathway, were assessed by immunoenzymatic assay in a total of 188 serial samples from 49 patients infected with SARS-CoV-2. Unlike C5a, neither C3bBbP nor C4d readouts rose proportionally to the severity of the disease. Detailed correlation analyses in hospitalization and follow-up samples collected from patients of different disease severity showed significant positive correlations of AP and CP/LP markers with C5a in certain groups, except for the follow-up samples of the patients who suffered from highly severe COVID-19 and presented the highest C5a readouts. In conclusion, there is not a clear link between persistently high levels of C5a after hospital discharge and markers of upstream complement activation, suggesting the existence of a non-canonical source of C5a in patients with a severe course of COVID-19.
  • Autores: Teijeira Sánchez, Álvaro; Garasa, S.; Luri Rey, Carlos; et al.
    Revista: CANCER RESEARCH
    ISSN: 1538-7445 Vol.82 N° 23 2022 págs. 4373 - 4385
    Resumen
    The ability of conventional type-1 dendritic cells (cDC1) to cross-present tumor antigens to CD8+ T cells is critical for the induction of antitumor cytotoxic T lymphocytes. Mice that are constitutively deficient in cDC1 cells have been reported to fail to respond to immunotherapy strategies based on checkpoint inhibitors. However, further work is needed to clarify the precise time during immunotherapy treatment that cDC1 cells are required for the beneficial effect of treatment. Here, we used a refined XCR1-DTR-Venus transgenic mouse model to acutely deplete cDC1 cells and trace their behavior using intravital microscopy. Diphtheria toxin-mediated cDC1 depletion prior to immunotherapy treatment with anti-PD-1 and/or anti-CD137 immunostimulatory monoclonal antibodies (mAbs) completely ablated anti-tumor efficacy. The efficacy of adoptive T-cell therapy was also hampered by prior cDC1 depletion. After the onset of immunotherapy treatment, depletion of cDC1s only moderately reduced the therapeutic efficacy of anti-PD-1 and anti-CD137 mAbs. Intravital microscopy of liver-engrafted tumors revealed changes in the intratumoral behavior of cDC1 cells in mice receiving immunotherapy, and treatment with diphtheria toxin to deplete cDC1s impaired tumor T-cell infiltration and function. These results reveal that the functional integrity of the cDC1 compartment is required at the onset of various immunotherapies to successfully treat established tumors.
  • Autores: Ascierto, P. A. (Autor de correspondencia); Avallone, A.; Bhardwaj, N.; et al.
    Revista: JOURNAL OF TRANSLATIONAL MEDICINE
    ISSN: 1479-5876 Vol.20 N° 1 2022 págs. 257
    Resumen
    Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies. The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.
  • Autores: Labiano Almiñana, Sara (Autor de correspondencia); Serrano Mendioroz, Irantzu; Rodríguez Ruiz, María Esperanza (Autor de correspondencia)
    Revista: METHODS IN CELL BIOLOGY
    ISSN: 0091-679X Vol.172 2022 págs. 179 - 189
    Resumen
    The rapid proliferation of cancer cells and the aberrant vasculature present in most solid tumors frequently result in the lack of oxygen generating a hypoxic tumor microenvironment. Low levels of oxygen not only affect the tumor cell biology and tumorigenesis, but also the other components of the tumor microenvironment such as the tumor stroma and the immune infiltrate, promoting a more suppressive environment. In addition, tumor hypoxia has been associated with reduced sensitivity to chemotherapy (CH) and radiotherapy (RT), leading to poor outcomes in cancer patients. Therefore, the evaluation of tumor oxygen status has become clinically relevant. Tumor hypoxia can be assessed by different methods that include the analysis of the oxygen concentration or the expression of endogenous markers directly related to hypoxia. In this paper, we focus on the use of the hypoxia-specific marker pimonidazole as a straightforward way to measure tumor hypoxia following radiotherapy in a preclinical melanoma model.
  • Autores: Glez-Vaz, J.; Azpilikueta, A.; Olivera, I.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.10 N° 3 2022 págs. e003532
    Resumen
    Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.
  • Autores: Olivera, I.; Sanz-Pamplona, R.; Bolaños Mateo, Elixabet; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.12 N° 9 2022 págs. 2140 - 2157
    Resumen
    Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNF alpha and IL-1 beta upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNF alpha and IL-1 beta induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNF alpha blockers infliximab and etanercept or the IL-1 beta inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNF alpha blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated. SIGNIFICANCE IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNF alpha and IL-1 beta are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents.
  • Autores: Rodríguez Ruiz, María Esperanza; Serrano Mendioroz, Irantzu; Garate Soraluze, Eneko; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Melero Bermejo, Ignacio; Yau, T.; Kang, Y.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° Supl. 4 2022 págs. S361
  • Autores: Rodríguez-Moreno, J. F.; Ruiz-Llorente, S.; De Velasco, G.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 6 2022
  • Autores: Albarrán-Artahona, V.; Torres-Jiménez, J.; Auclin, E.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.17 N° 9 2022 págs. S474 - S475
  • Autores: Girard, N.; Popat, S.; Shoshkova, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S1027 - S1028
  • Autores: Melero Bermejo, Ignacio; De Miguel, M. J.; Casal, G. A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S876 - S876
  • Autores: Hamilton, E. P.; Melero Bermejo, Ignacio; Lugowska, I.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S897 - S898
  • Autores: Rohrberg, K. S.; Garralda, E.; Calvo, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S884 - S885
  • Autores: Ascierto, P. A.; Mandala, M.; Ferrucci, P. F.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S1408 - S1409
  • Autores: Gutiérrez, M.; Friedman, C. F.; Long, G. V.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 7 2022 págs. S882 - S882
  • Autores: Gonzalez Vaz, Javier; Azpilicueta Lusarreta, Arantza; Olivera, I.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Ascierto, P. A.; Mandala, M.; Ferrucci, P. F.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022
    Resumen
    Background: To investigate the best sequential strategy, we started the SECOMBIT study, a randomized three parallel arms phase 2 study (NCT02631447). We used the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) and the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). We explored the two different sequences and the ¿sandwich¿ strategy with a short course of target therapy, switched by combo immunotherapy at the best response, and not at progression of disease. In our previous report we have observed a trend in favor of the arms where I-O was given as first, confirmed by the first report of the DreamSeq study, a phase III study which compared the two different sequences with T-T and I-O. Here we updated the study data with a subgroup analysis. Methods: From Nov 2016 to May 2019, 37 centers in 9 countries enrolled 251 patients with untreated, metastatic BRAFV600 melanoma. Patients were randomized to Arm A [E+B until PD, followed by I+N], or Arm B (I+N until PD, followed by E+B) or Arm C (E+B for 8 weeks, followed by I+N until PD, followed by E+B). The overall survival (OS) is the primary endpoint of the study. Secondary endpoints included total progression-free survival (tPFS), 2- and 3-years survival rate, best overall response rate, duration of response, biomarkers evaluation. Results: The study primary endpoint was met in each arm with at least 30 patients alive at 24 months. The median follow-up estimated with the reverse Kaplan-Meier method was 37.1 months (IQR: 32.8-46.4). The OS at 2 and 3 years was calculated in the three arms for all patients, and in the subgroups normal or elevate LDH level and < 3 or ¿ 3 metastatic sites. OS and tPFS rates at 2 and 3 years are shown in the table. Conclusions: With a 37.1 months median follow-up, 2 and 3-years OS as well as tPFS rates are higher in Arm B and C. In line with recent findings, the SECOMBIT results confirm a better trend in favor of Arm B and C treatment sequence. The analysis of the secondary endpoints is ongoing.
  • Autores: Olivera, I.; Sanz-Pamplona, R.; Bolaños Mateo, Elixabet; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.82 N° 12 2022
  • Autores: Bella Carreño, Ángela; Di-Trani, C. A.; Fernandez-Sendin, M.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 5 2021 págs. 963
    Resumen
    Simple Summary Peritoneal carcinomatosis mouse models as a platform to test, improve and/or predict the appropriate therapeutic interventions in patients are crucial to providing medical advances. Here, we overview reported mouse models to explore peritoneal carcinomatosis in translational biomedical research. Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents.
  • Autores: Salas Benito, Diego (Autor de correspondencia); Pérez Gracia, José Luis; Ponz Sarvisé, Mariano; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.11 N° 6 2021 págs. 1353 - 1367
    Resumen
    Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non-small and small cell lung carcinomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes.Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.
  • Autores: Teijeira Sánchez, Álvaro (Autor de correspondencia); Garasa, S.; Ochoa Nieto, Maria del Carmen; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.27 N° 9 2021 págs. 2383 - 2393
    Resumen
    One of the most important mechanisms by which cancer fosters its own development is the generation of an immune microenvironment that inhibits or impairs antitumor immune responses. A cancer permissive immune microenvironment is present in a large proportion of the patients with cancer who do not respond to immunotherapy approaches intended to trigger preexisting antitumor immune responses, for instance, immune checkpoint blockade. High circulating levels of IL8 in patients with cancer quite accurately predict those who will not benefit from checkpoint-based immunotherapy. IL8 has been reported to favor cancer progression and metastases via different mechanisms, including proangiogenesis and the maintenance of cancer stem cells, but its ability to attract and functionally modulate neutrophils and macrophages is arguably one of the most important factors. IL8 does not only recruit neutrophils to tumor lesions, but also triggers the extrusion of neutrophil extracellular traps (NET). The relevance and mechanisms underlying the contribution of both neutrophils and NETs to cancer development and progression are starting to be uncovered and include both direct effects on cancer cells and changes in the tumor microenvironment, such as facilitating metastasis, awakening micrometastases from dormancy, and facilitating escape from cytotoxic immune cells. Blockade of IL8 or its receptors (CXCR1 and CXCR2) is being pursued in drug development, and clinical trials alone or in combination with anti-PD-L1 checkpoint inhibitors are already ongoing.
  • Autores: Da Silva Maia, Catarina Alexandra; Martín Sanchez, Esperanza; Garcés Latre, Juan José; et al.
    Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
    ISSN: 0390-6078 Vol.106 N° 5 2021 págs. 1457 - 1460
  • Autores: Melero Bermejo, Ignacio; Normanno, N. (Autor de correspondencia)
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° 11 2021 págs. 1311 - 1313
  • Autores: Castelo-Branco, L.; Awada, A.; Pentheroudakis, G. (Autor de correspondencia); et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.6 N° 5 2021 págs. 100237
  • Autores: Rodríguez Ruiz, María Esperanza; Fernández de Sanmamed Gutiérrez, Miguel; Serrano Mendioroz, Irantzu; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.27 N° 20 2021 págs. 5443 - 5445
    Resumen
    Radiotherapy and immunotherapy can be concomitantly or sequentially combined seeking synergistic effects in terms of control of irradiated tumors and abscopal effects on nonirradiated lesions. Clinical-trial testing of such combinations faces several obstacles to demonstrate efficacy and needs improvements in trial design, patient selection, evaluation of results and biomarker discovery.
  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Teijeira Sánchez, Álvaro; Aranda Vega, Fernando; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.11 N° 10 2021 págs. 2372 - 2374
    Resumen
    In this issue of Cancer Discovery, Pelly and colleagues show that inhibition of prostaglandin E-2 synthesis or its activity on EP2 and EP4 receptors synergizes with anti-PD-1 immunotherapy and triggers a potent intratumoral IFN gamma response in mouse models and in fresh surgical human tumor explants. This therapeutic strategy is in line with other interventions that aim at fostering immunotherapy by means of quenching protumor inflammation.
  • Autores: Sznol, M. (Autor de correspondencia); Melero Bermejo, Ignacio
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° 3 2021 págs. 295 - 297
  • Autores: Teijeira Sánchez, Álvaro (Autor de correspondencia); Garasa, S.; Ochoa, M. D.; et al.
    Revista: EUROPEAN JOURNAL OF IMMUNOLOGY
    ISSN: 0014-2980 Vol.51 N° 9 2021 págs. 2274 - 2280
    Resumen
    In humans, IL-8 (CXCL8) is a key chemokine for chemotaxis of polymorphonuclear leukocytes and monocytes/macrophages when acting on CXCR1 and CXCR2. CXCL8 activity on neutrophils includes chemotaxis and eliciting the extrusion of neutrophil extracellular traps (NETs). In this study, we show that concentrations of IL-8 that induce NETosis surpass in at least one order of magnitude those required to elicit chemoattraction in human neutrophils. IL-8-induced NETosis was less dependent on G-proteins than migration, while extracellular Ca+2 chelation similarly inhibited both processes. Reactive oxygen species (ROS) were more important for NETosis than for chemotaxis as evidenced by neutralization with N-acetyl -cysteine. Interestingly, selective blockade with anti-CXCR1 mAb inhibited NETosis much more readily than chemotaxis, while pharmacological inhibition of both CXCR1 and CXCR2, or selective inhibition for CXCR2 alone, similarly inhibited both functions. Together, these results propose a model according to which low concentrations of IL-8 in a gradient attract neutrophils to the inflammatory foci, while high receptor-saturating concentrations of IL-8 give rise to NETosis once leukocytes reach the core of the inflammatory insult.
  • Autores: Ardaiz Iriarte, Nuria María; Gomar Peláez, Celia; Vásquez Durán, Marcos Antonio; et al.
    Revista: FRONTIERS IN PHARMACOLOGY
    ISSN: 1663-9812 Vol.11 2021 págs. 591293
    Resumen
    Background: Targeting long-lasting insulins to the liver may improve metabolic alterations that are not corrected with current insulin replacement therapies. However, insulin is only able to promote lipogenesis but not to block gluconeogenesis in the insulin-resistant liver, exacerbating liver steatosis associated with diabetes. Methods: In order to overcome this limitation, we fused a single-chain insulin to apolipoprotein A-I, and we evaluated the pharmacokinetics and pharmacodynamics of this novel fusion protein in wild type mice and in db/db mice using both recombinant proteins and recombinant adenoassociated virus (AAV). Results: Here, we report that the fusion protein between single-chain insulin and apolipoprotein A-I prolonged the insulin half-life in circulation, and accumulated in the liver. We analyzed the long-term effect of these insulin fused to apolipoprotein A-I or insulin fused to albumin using AAVs in the db/db mouse model of diabetes, obesity, and liver steatosis. While AAV encoding insulin fused to albumin exacerbated liver steatosis in several mice, AAV encoding insulin fused to apolipoprotein A-I reduced liver steatosis. These results were confirmed upon daily subcutaneous administration of the recombinant insulin-apolipoprotein A-I fusion protein for six weeks. The reduced liver steatosis was associated with reduced body weight in mice treated with insulin fused to apolipoprotein A-I. Recombinant apolipoprotein A-I alone significantly reduces body weight and liver weight, indicating that the apolipoprotein A-I moiety is the main driver of these effects. Conclusion: The fusion protein of insulin and apolipoprotein A-I could be a promising insulin derivative for the treatment of diabetic patients with associated fatty liver disease.
  • Autores: Arce, C.; Rodríguez-Rovira, I.; De-Rycke, K.; et al.
    Revista: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
    ISSN: 1079-5642 Vol.41 N° 9 2021 págs. e440 - e452
    Resumen
    Objective: We investigated the effect of a potent TGF beta (transforming growth factor beta) inhibitor peptide (P144) from the betaglycan/TGF beta receptor III on aortic aneurysm development in a Marfan syndrome mouse model. Approach and Results: We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGF beta signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgf beta 1 and Tgf beta 2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGF beta signaling. Unlike the palliative treatment, the preventive treatment reduced Tgf beta 1 and Tgf beta 2 mRNA levels. Conclusions: P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGF beta signaling during the early stages of aortic disease progression.
  • Autores: Tenesaca Cayambe, Shirley; Vásquez Durán, Marcos Antonio; Alvarez Rodriguez, Maite; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 7 2021 págs. e001587
    Resumen
    Background Modified vaccinia virus Ankara (MVA) are genetically engineered non-replicating viral vectors. Intratumoral administration of MVA induces a cyclic GMP-AMP synthase-mediated type I interferon (IFN) response and the production of high levels of the transgenes engineered into the viral genome such as tumor antigens to construct cancer vaccines. Although type I IFNs are essential for establishing CD8-mediated antitumor responses, this cytokine family may also give rise to immunosuppressive mechanisms. Methods In vitro assays were performed to evaluate the activity of simvastatin and atorvastatin on type I IFN signaling and on antigen presentation. Surface levels of IFN alpha/beta receptor 1, endocytosis of bovine serum albumin-fluorescein 5 (6)-isothiocyanate, signal transducer and activator of transcription (STAT) phosphorylation, and real-time PCR of IFN-stimulated genes were assessed in the murine fibroblast cell line L929. In vivo experiments were performed to characterize the effect of simvastatin on the MVA-induced innate immune response and on the antitumor effect of MVA-based antitumor vaccines in B16 melanoma expressing ovalbumin (OVA) and Lewis lung carcinoma (LLC)-OVA tumor models. RNAseq analysis, depleting monoclonal antibodies, and flow cytometry were used to evaluate the MVA-mediated immune response. Results In this work, we identified commonly prescribed statins as potent IFN alpha pharmacological inhibitors due to their ability to reduce surface expression levels of IFN-alpha/beta receptor 1 and to reduce clathrin-mediated endocytosis. Simvastatin and atorvastatin efficiently abrogated for 8 hours the transcriptomic response to IFN alpha and enhanced the number of dendritic cells presenting an OVA-derived peptide bound to major histocompatibility complex (MHC) class I. In vivo, intraperitoneal or intramuscular administration of simvastatin reduced the inflammatory response mediated by peritumoral administration of MVA and enhanced the antitumor activity of MVA encoding tumor-associated antigens. The synergistic antitumor effects critically depend on CD8(+) cells, whereas they were markedly improved by depletion of CD4(+) lymphocytes, T regulatory cells, or NK cells. Either MVA-OVA alone or combined with simvastatin augmented B cells, CD4(+) lymphocytes, CD8(+) lymphocytes, and tumor-specific CD8(+) in the tumor-draining lymph nodes. However, only the treatment combination increased the numbers of these lymphocyte populations in the tumor microenvironment and in the spleen. Conclusion In conclusion, blockade of IFN alpha functions by simvastatin markedly enhances lymphocyte infiltration and the antitumor activity of MVA, prompting a feasible drug repurposing.
  • Autores: Zalba Oteiza, Sara; Belsúe Urquizu, Virginia; Topp, B.; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN: 0007-0920 Vol.124 N° 7 2021 págs. 1275 - 1285
    Resumen
    Background Anti-programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibodies (mAbs) show remarkable clinical anti-tumour efficacy. However, rational combinations are needed to extend the clinical benefit to primary resistant tumours. The design of such combinations requires the identification of the kinetics of critical immune cell populations in the tumour microenvironment. Methods In this study, we compared the kinetics of immune cells in the tumour microenvironment upon treatment with immunotherapy combinations with different anti-tumour efficacies in the non-inflamed tumour model TC-1/A9. Tumour-bearing C57BL/6J mice were treated with all possible combinations of a human papillomavirus (HPV) E7 long peptide, polyinosinic-polycytidylic acid (PIC) and anti-PD-1 mAb. Tumour growth and kinetics of the relevant immune cell populations were assessed over time. The involvement of key immune cells was confirmed by depletion with mAbs and immunophenotyping with multiparametric flow cytometry. Results The maximum anti-tumour efficacy was achieved after intratumoural administration of HPV E7 long peptide and PIC combined with the systemic administration of anti-PD-1 mAb. The intratumoural immune cell kinetics of this combination was characterised by a biphasic immune response. An initial upsurge of proinflammatory myeloid cells led to a further rise in effector CD8(+) T lymphocytes at day 8. Depletion of either myeloid cells or CD8(+) T lymphocytes diminished the anti-tumour efficacy of the combination. Conclusions The anti-tumour efficacy of a successful immunotherapy combination in a non-inflamed tumour model relies on an early inflammatory process that remodels the myeloid cell compartment.
  • Autores: Cueto, F. J.; Del Fresno, C.; Brandi, P.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 5 2021 págs. e002054
    Resumen
    Background Conventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet. Methods B16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s. Results Here, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8(+) T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth. Conclusion DNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.
  • Autores: Gutierrez, M. (Autor de correspondencia); Moreno, V.; Heinhuis, K. M. ; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.27 N° 2 2021 págs. 460 - 472
    Resumen
    Purpose: This phase I/IIa study (NCT02737475) evaluated the safety and activity of BMS-986178, a fully human OX40 agonist IgG1 mAb, +/- nivolumab and/or ipilimumab in patients with advanced solid tumors. Patients and Methods: Patients (with non-small cell lung, renal cell, bladder, other advanced cancers) received BMS-986178 (20-320 mg) +/- nivolumab (240-480 mg) and/or ipilimumab (1-3 mg/kg). The primary endpoint was safety. Additional endpoints included immunogenicity, pharmacodynamics, pharmacokinetics, and antitumor activity per RECIST version 1.1. Results: Twenty patients received BMS-986178 monotherapy, and 145 received combination therapy in various regimens (including two patients receiving nivolumab monotherapy). With a followup of 1.1 to 103.6 weeks, the most common (>= 5%) treatment-related adverse events (TRAEs) included fatigue, pruritus, rash, pyrexia, diarrhea, and infusion-related reactions. Overall, grade 3-4 TRAEs occurred in one of 20 patients (5%) receiving BMS-986178 monotherapy, six of 79 (8%) receiving BMS-986178 plus nivolumab, zero of two receiving nivolumab monotherapy, six of 41 (15%) receiving BMS-986178 plus ipilimumab, and three of 23 (13%) receiving BMS-986178 plus nivolumab plus ipilimumab. No deaths occurred. No dose-limiting toxicities were observed with monotherapy, and the MTD was not reached in either the monotherapy or the combination escalation cohorts. No objective responses were seen with BMS-986178 alone; objective response rates ranged from 0% to 13% across combination therapy cohorts. Conclusions: In this study, BMS-986178 +/- nivolumab and/or ipilimumab appeared to have a manageable safety profile, but no clear efficacy signal was observed above that expected for nivolumab and/or ipilimumab.
  • Autores: Sanegre, S.; Eritja, N.; De Andrea, Carlos Eduardo; et al.
    Revista: FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
    ISSN: 2296-634X Vol.9 2021 págs. 670185
    Resumen
    The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
  • Autores: Segues, A.; van Duijnhoven, S. M. J.; Parade, M.; et al.
    Revista: JOURNAL OF IMMUNOLOGICAL METHODS
    ISSN: 0022-1759 Vol.499 2021 págs. 113173
    Resumen
    Tumor necrosis factor receptor 2 (TNFR2) has gained much research interest in recent years because of its potential pivotal role in autoimmune disease and cancer. However, its function in regulating different immune cells is not well understood. There is a need for well-characterized reagents to selectively modulate TNFR2 function, thereby enabling definition of TNFR2-dependent biology in human and mouse surrogate models. Here, we describe the generation, production, purification, and characterization of a panel of novel antibodies targeting mouse TNFR2. The antibodies display functional differences in binding affinity and potency to block TNF alpha. Furthermore, epitope binding showed that the anti-mTNFR2 antibodies target different domains on the TNFR2 protein, associated with varying capacity to enhance CD8(+) T-cell activation and costimulation. Moreover, the anti-TNFR2 antibodies demonstrate binding to isolated splenic mouse Tregs ex vivo and activated CD8(+) cells, reinforcing their potential use to establish TNFR2-dependent immune modulation in translational models of autoimmunity and cancer.
  • Autores: Greten, T. F. (Autor de correspondencia); Abou-Alfa, G. K.; Cheng, A. L.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 9 2021 págs. e002794
    Resumen
    Patients with advanced hepatocellular carcinoma (HCC) have historically had few options and faced extremely poor prognoses if their disease progressed after standard-of-care tyrosine kinase inhibitors (TKIs). Recently, the standard of care for HCC has been transformed as a combination of the immune checkpoint inhibitor (ICI) atezolizumab plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was shown to offer improved overall survival in the first-line setting. Immunotherapy has demonstrated safety and efficacy in later lines of therapy as well, and ongoing trials are investigating novel combinations of ICIs and TKIs, in addition to interventions earlier in the course of disease or in combination with liver-directed therapies. Because HCC usually develops against a background of cirrhosis, immunotherapy for liver tumors is complex and oncologists need to account for both immunological and hepatological considerations when developing a treatment plan for their patients. To provide guidance to the oncology community on important concerns for the immunotherapeutic care of HCC, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for HCC, including diagnosis and staging, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with HCC.
  • Autores: Hinterberger, M. (Autor de correspondencia); Giessel, R.; Fiore, G.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 2 2021 págs. e001586
    Resumen
    Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host ' s inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8(+) T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment. Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy. Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8(+) T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA. Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8(+) T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.
  • Autores: Etxeberria Uriz, Iñaki; Bolaños Mateo, Elixabet; Teijeira Sánchez, Álvaro; et al.
    Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
    ISSN: 0027-8424 Vol.118 N° 26 2021 págs. e2025930118
    Resumen
    Costimulation via CD137 (4-1BB) enhances antitumor immunity mediated by cytotoxic T lymphocytes. Anti-CD137 agonist antibodies elicit mild liver inflammation in mice, and the maximum tolerated dose of Urelumab, an anti-human CD137 agonist monoclonal antibody, in the clinic was defined by liver inflammation-related side effects. A protease-activated prodrug form of the anti-mouse CD137 agonist antibody 1D8 (1D8 Probody therapeutic, Pb-Tx) was constructed and found to be selectively activated in the tumor microenvironment. This construct, which encompasses a protease-cleavable linker holding in place a peptide that masks the antigen binding site, exerted antitumor effects comparable to the unmodified antibody but did not result in liver inflammation. Moreover, it efficaciously synergized with both PD-1 blockade and adoptive T-cell therapy. Surprisingly, minimal active Pb-Tx reached tumor-draining lymph nodes, and regional lymphadenectomy did not abrogate antitumor efficacy. By contrast, S1P receptor-dependent recirculation of T cells was absolutely required for efficacy. The preferential cleavage of the anti-CD137 Pb-Tx by tumor proteases offers multiple therapeutic opportunities, including neoadjuvant therapy, as shown by experiments in which the Pb-Tx is given prior to surgery to avoid spontaneous metastases.
  • Autores: Cabo, M.; Santana-Hernández, S.; Costa-García, M.; et al.
    Revista: CANCER IMMUNOLOGY RESEARCH
    ISSN: 2326-6066 Vol.9 N° 12 2021 págs. 1476 - 1490
    Resumen
    Enhancing natural killer (NK) cell-based cancer immunotherapy by overcoming immunosuppression is an area of intensive research. Here, we have demonstrated that the anti-CD137 agonist urelumab can overcome TGFb-mediated inhibition of human NK-cell proliferation and antitumor function. Transcriptomic, immunophenotypic, and functional analyses showed that CD137 costimulation modified the transcriptional program induced by TGFb on human NK cells by rescuing their proliferation in response to IL2, preserving their expression of activating receptors (NKG2D) and effector molecules (granzyme B, IFN gamma) while allowing the acquisition of tumor-homing/retention features (CXCR3, CD103). Activated NK cells cultured in the presence of TGFb1 and CD137 agonist recovered CCL5 and IFN gamma secretion and showed enhanced direct and antibody-dependent cytotoxicity upon restimulation with cancer cells. Trastuzumab treatment of fresh breast carcinoma-derived multicellular cultures induced CD137 expression on tumor-infiltrating CD16(+) NK cells, enabling the action of urelumab, which fostered tumor-infiltrating NK cells and recapitulated the enhancement of CCL5 and IFN gamma production. Bioinformatic analysis pointed to IFNG as the driver of the association between NK cells and clinical response to trastuzumab in patients withHER2-positive primary breast cancer, highlighting the translational relevance of the CD137 costimulatory axis for enhancing IFN gamma production. Our data reveals CD137 as a targetable checkpoint for overturning TGF beta constraints on NK-cell antitumor responses.
  • Autores: Bedke, J. (Autor de correspondencia); Merseburger, A. S.; Loriot, Y.; et al.
    Revista: EUROPEAN UROLOGY FOCUS
    ISSN: 2405-4569 Vol.7 N° 5 2021 págs. 1084 - 1091
    Resumen
    Background: The value of a complete response to immune checkpoint inhibitor treat-ment for urothelial cancer is well recognised, but less is known about long-term outcomes in patients with a partial response or the benefit of achieving disease stabilisation. Objective: To determine clinical outcomes in patients with a partial response or stable disease on atezolizumab therapy for advanced urinary tract carcinoma (UTC). Design, setting, and participants: Data were extracted from three prospective trials (IMvigor210 cohort 2, SAUL, and IMvigor211) evaluating single-agent atezolizumab therapy for platinum-pretreated advanced UTC. The analysis population included 604 atezolizumab-treated and 208 chemotherapy-treated patients (229 achieving a partial response and 583 achieving stable disease). Intervention: Atezolizumab 1200 mg every 3 wk until progression or unacceptable toxicity or single-agent chemotherapy for patients in the control arm of IMvigor211. Outcome measurements and statistical analysis: Baseline characteristics, treatment exposure, overall survival, duration of disease control. Partial response and stable disease populations were analysed separately. Results and limitations: The population of patients with a partial response included more patients with programmed cell death ligand 1 (PD-L1) expression on >5% of tumour-infiltrating immune cells than the stable disease population. The median time to best response was 2.1 mo across trials and treatments, regardless of the type of response. Atezolizumab-treated patients with a partial response had sustained disease control (median overall survival not reached); durations of disease control and overall survival were longer with atezolizumab than with chemotherapy. In patients with stable disease, median overall survival was numerically longer with atezolizumab (exceeding 1 yr) than with chemotherapy. Irrespective of treatment, durations of disease control and survival were shorter in patients with stable disease than in those achieving a partial response. These analyses are limited by their post hoc exploratory nature and relatively short follow-up. Conclusions: Stable disease and partial response are meaningful clinical outcomes in atezolizumab-treated patients with advanced UTC. Patient summary: In this report, we looked at the outcomes in patients whose tumours responded to treatment to some extent, but the tumour did not disappear completely. We aimed to understand whether a modest response to treatment was associated with meaningful long-term outcomes for patients. We found that on average, life expectancy was >1 yr in patients whose disease was stabilised and even longer in those whose tumours showed some shrinkage in response to treatment. (c) 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
  • Autores: Alvarez Rodriguez, Maite; Molina Samper, Carmen; De Andrea, Carlos Eduardo; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° 11 2021 págs. e002953
    Resumen
    Background BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid that acting on toll-like receptor 3 (TLR3), melanoma differentiation-associated protein 5 (MDA5) and protein kinase RNA-activated (PKR) elicits rejection of directly injected transplanted tumors, but has only modest efficacy against distant untreated tumors. Its clinical activity has also been documented in early phase clinical trials. The 5,6-dimethylxanthenone-4-acetic acid (DMXAA) stimulator of interferon genes (STING) agonist shows a comparable pattern of efficacy when used via intratumoral injections. Methods Mice subcutaneously engrafted with bilateral MC38 and B16.OVA-derived tumors were treated with proinflammatory immunotherapy agents known to be active when intratumorally delivered. The combination of BO-112 and DMXAA was chosen given its excellent efficacy and the requirements for antitumor effects were studied on selective depletion of immune cell types and in gene-modified mouse strains lacking basic leucine zipper ATF-like transcription factor 3 (BATF3), interferon-alpha/beta receptor (IFNAR) or STING. Spatial requirements for the injections were studied in mice bearing three tumor lesions. Results BO-112 and DMXAA when co-injected in one of the lesions of mice bearing concomitant bilateral tumors frequently achieved complete local and distant antitumor efficacy. Synergistic effects were contingent on CD8 T cell lymphocytes and dependent on conventional type 1 dendritic cells, responsiveness to type I interferon (IFN) and STING function in the tumor-bearing host. Efficacy was preserved even if BO-112 and DMXAA were injected in separate lesions in a manner able to control another untreated third-party tumor. Efficacy could be further enhanced on concurrent PD-1 blockade. Conclusion Clinically feasible co-injections of BO-112 and a STING agonist attain synergistic efficacy able to eradicate distant untreated tumor lesions.
  • Autores: Otano Andrés, Itziar (Autor de correspondencia); Azpilicueta Lusarreta, Arantza; Gonzalez Vaz, Javier; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.12 N° 1 2021 págs. 7296
    Resumen
    CD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-kappa B signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans. Costimulation has been shown to be required for optimal activation of T cells and it could be delivered either in trans with respect to the source of CD3-TCR ligation or in cis on the same cell. Here the authors show that CD137 costimulation is more effective when delivered in cis to enhance T cell proliferation and activation.
  • Autores: Patiño García, Ana; Guruceaga Martínez, Elisabet; Segura Ruiz, Victor; et al.
    Revista: TRANSLATIONAL LUNG CANCER RESEARCH
    ISSN: 2218-6751 Vol.10 N° 3 2021 págs. 1327 - +
    Resumen
    Background: Tobacco is the main risk factor for developing lung cancer. Yet, some heavy smokers do not develop lung cancer at advanced ages while others develop it at young ages. Here, we assess for the first time the genetic background of these clinically relevant extreme phenotypes using whole exome sequencing (WES). Methods: We performed WES of germline DNA from heavy smokers who either developed lung adenocarcinoma at an early age ( extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (extreme controls, n=50). We selected non-synonymous variants located in exonic regions and consensus splice sites of the genes that showed significantly different allelic frequencies between both cohorts. We validated our results in all the additional extreme cases (i.e., heavy smokers who developed lung adenocarcinoma at an early age) available from The Cancer Genome Atlas (TCGA). Results: The mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.6 and 56.8 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 108 of these in extreme cases selected from TCGA. Nine validated variants, located in relevant cancer related genes, such as PARP4, HLA-A or NQO1, among others, achieved statistical significance in the False Discovery Rate test. The most significant validated variant (P=4.48x10(-5)) was located in the tumor-suppressor gene ALPK2. Conclusions: We describe genetic variants associated with extreme phenotypes of high and low risk for the development of tobacco-induced lung adenocarcinoma. Our results and our strategy may help to identify high-risk subjects and to develop new therapeutic strategies.
  • Autores: Merino Díaz, María; Lozano Moreda, Teresa; Casares Lagar, Noelia; et al.
    Revista: JOURNAL OF NANOBIOTECHNOLOGY
    ISSN: 1477-3155 Vol.19 N° 1 2021 págs. 102
    Resumen
    Background: The immunomodulation of the antitumor response driven by immunocheckpoint inhibitors (ICIs) such as PD-L1 (Programmed Death Ligand-1) monoclonal antibody (alpha-PD-L1) have shown relevant clinical outcomes in a subset of patients. This fact has led to the search for rational combinations with other therapeutic agents such as Doxorubicin (Dox), which cytotoxicity involves an immune activation that may enhance ICI response. Therefore, this study aims to evaluate the combination of chemotherapy and ICI by developing Dox Immunoliposomes functionalized with monovalent-variable fragments (Fab') of alpha-PD-L1. Results: Immunoliposomes were assayed in vitro and in vivo in a B16 OVA melanoma murine cell line over-expressing PD-L1. Here, immune system activation in tumor, spleen and lymph nodes, together with the antitumor efficacy were evaluated. Results showed that immunoliposomes bound specifically to PD-L1(+) cells, yielding higher cell interaction and Dox internalization, and decreasing up to 30-fold the IC50, compared to conventional liposomes. This mechanism supported a higher in vivo response. Indeed, immunoliposomes promoted full tumor regression in 20% of mice and increased in 1 month the survival rate. This formulation was the only treatment able to induce significant (p < 0.01) increase of activated tumor specific cytotoxic T lymphocytes at the tumor site. Conclusion: PD-L1 targeted liposomes encapsulating Dox have proved to be a rational combination able to enhance the modulation of the immune system by blocking PD-L1 and selectively internalizing Dox, thus successfully providing a dual activity offered by both, chemo and immune therapeutic strategies.
  • Autores: Fernández de Sanmamed Gutiérrez, Miguel; Nie, X. X.; Desai, S. S.; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.11 N° 7 2021 págs. 1700 - 1715
    Resumen
    Specific mechanisms by which tumor-infiltrating lymphocytes (TIL) become dysfunctional remain poorly understood. Here, we employed a two-pronged approach using single-cell mass cytometry and tissue imaging technologies to dissect TILs from 25 patients with resectable and 35 patients with advanced non-small cell lung cancer (NSCLC). We identified a burned-out CD8(+) TIL subset (Ebo) that specifically accumulated within the tumor microenvironment (TME) but not in adjacent nontumoral tissues. Ebo showed the highest expression of proliferation and activation markers but produced the lowest amount of IFN gamma and were the most apoptotic CD8(+) TIL subset. Using a humanized patient-derived tumor xenograft model, we demonstrated that Ebo expansion occurred within the TME in a PD-1/B7-H1 pathway-dependent manner. Ebo abundance in baseline tumor tissues was associated with resistance to anti-PD therapy in patients with NSCLC. Our study identifies a dysfunctional TIL subset, with distinct features from previously described exhausted T cells, and implies strategies to overcome immunotherapy resistance. SIGNIFICANCE: We identified a highly proliferative, overactivated, and apoptotic dysfunctional CD8(+) tumor-infiltrating subpopulation that is functionally distinct from previously described exhausted T cells. This population is expanded in lung cancer tissues in a PD-1/B7-H1-dependent manner, and its abundance is associated with resistance to cancer immunotherapy, thus becoming a potential tissue biomarker.
  • Autores: De Andrea, Carlos Eduardo; Ochoa Nieto, Maria del Carmen; Villalba Esparza, María; et al.
    Revista: JOURNAL OF PATHOLOGY
    ISSN: 0022-3417 Vol.255 N° 2 2021 págs. 190 - 201
    Resumen
    Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8(+) T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8(+) T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8(+) T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8(+) tumour-infiltrating lymphocytes. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
  • Autores: Downes, D. J.; Cross, A. R.; Hua, P.; et al.
    Revista: NATURE GENETICS
    ISSN: 1061-4036 Vol.53 N° 11 2021 págs. 1606 - 1615
    Resumen
    The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1). Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target. SNP rs17713054 in the 3p21.31 COVID-19 risk locus is identified as a probable causative variant for disease association. Chromatin conformation and gene expression data indicate that LZTFL1 is impacted by rs17713054 in pulmonary epithelial cells.
  • Autores: Herbst, R. S. (Autor de correspondencia); Garon, E. B.; Kim, D. W.; et al.
    Revista: RESEARCH IN SOCIAL AND ADMINISTRATIVE PHARMACY
    ISSN: 1551-7411 Vol.16 N° 10 2021 págs. 1718 - 1732
    Resumen
    Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) >= 50% and >= 1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study. Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m(2) once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis. Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0-77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44. 0.69) for patients with PD-L1 TPS >= 50% and 0.70 (0.61. 0.80) with PD-L1 TPS >= 1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS >= 50% and 15.6% versus 6.5% with PD-L1 TPS >= 1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (similar to 5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (>= 175 mutations per exome) was associated with improved outcomes with pembrolizumab. Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS >= 50% and >= 1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting. (C) 2021 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer.
  • Autores: Fernandez-Sendin, M.; Di Trani, C. A.; Bella Carreño, Ángela; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.11 2021 págs. 620283
    Resumen
    Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFN alpha). Long-term IFN alpha expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFN alpha expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFN alpha and interferon-stimulated genes were observed in mice treated with AAV-IFN alpha alone and in mice treated with AAV-IFN alpha and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFN alpha modulated the gene expression program of IFN alpha, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPAR alpha/gamma nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFN alpha expression mediated by an adeno-associated virus.
  • Autores: Compte, M.; Harwood, S. L.; Erce-Llamazares, A.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.27 N° 11 2021 págs. 3167 - 3177
    Resumen
    Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell-mediated antitumor response. Systemic administration of anti-4-1BB-agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity. Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain. It was characterized by structural analysis and in vitro functional studies. We also assessed pharmacokinetics, antitumor efficacy, and toxicity in vivo. Results: In the presence of a T-cell receptor signal, the trimerbody provided potent T-cell costimulation that was strictly dependent on 4-1BB hyperclustering at the point of contact with a tumor antigen-displaying cell surface. It exhibits significant antitumor activity in vivo, without hepatotoxicity, in a wide range of human tumors including colorectal and breast cancer cell-derived xenografts, and non-small cell lung cancer patient-derived xenografts associated with increased tumor-infiltrating CD8(+) T cells. The combination of the trimerbody with a PD-L1 blocker led to increased IFN gamma secretion in vitro and resulted in tumor regression in humanized mice bearing aggressive triple-negative breast cancer. Conclusions: These results demonstrate the nontoxic broad antitumor activity of humanized Fc-free tumor-specific 4-1BB-agonistic trimerbodies and their synergy with checkpoint blockers, which may provide a way to elicit responses in most patients with cancer while avoiding Fc-mediated adverse reactions.
  • Autores: Metzger, O.; Lambertini, C.; Krop, I. E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 2 2021 págs. S37 - S38
  • Autores: Davar, D.; Sweis, R. F.; Blumenschein, G. (Jr.); et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Suppl. 7 2021 págs. S1411 - S1413
  • Autores: Petrylak, D. P.; Pérez Gracia, José Luis; Lacombe, L.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S629 - S630
  • Autores: Alsina, M.; Ponz Sarvisé, Mariano; García, D. L.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Melero Bermejo, Ignacio; Calvo Aller, Emiliano; Dummer, R.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Melero Bermejo, Ignacio; Calvo, E.; Goebeler, M. E.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° Supl. 2 2021 págs. A536
  • Autores: Ponce Aix, S.; Calvo, E.; Moreno, V.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.9 N° Suppl. 2 2021 págs. A546 - A546
  • Autores: Alvarez Rodriguez, Maite; Molina Samper, Carmen; Fernández Sendín, M.; et al.
    Revista: EUROPEAN JOURNAL OF IMMUNOLOGY
    ISSN: 0014-2980 Vol.51 N° Supl. 1 2021 págs. 124 - 124
  • Autores: Melero Bermejo, Ignacio; Geva, R.; Ben-Ami, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 2021 págs. S313 - S313
  • Autores: Herbst, R.; Garon, E.; Kim, D.; et al.
    Revista: JOURNAL OF THORACIC ONCOLOGY
    ISSN: 1556-0864 Vol.16 N° 3 2021 págs. S223 - S224
  • Autores: Garralda, E.; Melero Bermejo, Ignacio; de Velasco, G.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 2021 págs. S1454 - S1454
  • Autores: Otano Andrés, Itziar; Azpilicueta Lusarreta, Arantza; Gonzalez Vaz, Javier; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 13 2021
  • Autores: Girard, N.; Popat, S.; Shoshkova, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 7 2021 págs. S1418 - S1419
  • Autores: Alsina, M.; Ponz Sarvisé, Mariano; López-García, D.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 3 2021 págs. S155 - S156
  • Autores: Rodríguez Márquez, Paula; Calleja Cervantes, María Erendira; SERRANO SANZ, Guillermo; et al.
    Revista: HUMAN GENE THERAPY
    ISSN: 1043-0342 Vol.32 N° 19-20 2021 págs. A37 - A38
  • Autores: Pérez-Ruiz, E.; Melero Bermejo, Ignacio; Kopecka, J.; et al.
    Revista: DRUG RESISTANCE UPDATES
    ISSN: 1368-7646 Vol.53 2020 págs. 100718
    Resumen
    Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases. However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer. While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host. Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed. Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3 gamma or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance. This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance.
  • Autores: Rodríguez Ruiz, María Esperanza; Vitale, I.; Harrington, K. J.; et al.
    Revista: NATURE IMMUNOLOGY
    ISSN: 1529-2908 Vol.21 N° 2 2020 págs. 120 - 134
    Resumen
    Radiation therapy has for decades been a standard form of treatment for many cancers. A Review by Galluzzi and colleagues explores the effects of radiation therapy in the context of the immune response. Therapeutic irradiation of the tumor microenvironment causes differential activation of pro-survival and pro-death pathways in malignant, stromal, endothelial and immune cells, hence causing a profound cellular and biological reconfiguration via multiple, non-redundant mechanisms. Such mechanisms include the selective elimination of particularly radiosensitive cell types and consequent loss of specific cellular functions, the local release of cytokines and danger signals by dying radiosensitive cells, and altered cytokine secretion by surviving radioresistant cells. Altogether, these processes create chemotactic and immunomodulatory cues for incoming and resident immune cells. Here we discuss how cytoprotective and cytotoxic signaling modules activated by radiation in specific cell populations reshape the immunological tumor microenvironment.
  • Autores: Etxeberria Uriz, Iñaki (Autor de correspondencia); Olivera, I.; Bolaños Mateo, Elixabet; et al.
    Revista: CELLULAR AND MOLECULAR IMMUNOLOGY
    ISSN: 1672-7681 Vol.17 N° 6 2020 págs. 576 - 586
    Resumen
    Gene engineering and combinatorial approaches with other cancer immunotherapy agents may confer capabilities enabling full tumor rejection by adoptive T cell therapy (ACT). The provision of proper costimulatory receptor activity and cytokine stimuli, along with the repression of inhibitory mechanisms, will conceivably make the most of these treatment strategies. In this sense, T cells can be genetically manipulated to become refractory to suppressive mechanisms and exhaustion, last longer and differentiate into memory T cells while endowed with the ability to traffic to malignant tissues. Their antitumor effects can be dramatically augmented with permanent or transient gene transfer maneuvers to express or delete/repress genes. A combination of such interventions seeks the creation of the ultimate bionic T cell, perfected to seek and destroy cancer cells upon systemic or local intratumor delivery.
  • Autores: López Janeiro, Álvaro (Autor de correspondencia); Padilla-Ansala, C.; De Andrea, Carlos Eduardo; et al.
    Revista: MODERN PATHOLOGY
    ISSN: 0893-3952 Vol.33 N° 8 2020 págs. 1458 - 1465
    Resumen
    Macrophage polarization is relevant for tumor biology. M2 polarized macrophages favor tumor growth and survival, while M1 macrophages support tumor destruction and antigen presentation. Markers identifying M1/M2 polarization are a subject of debate. We conducted a systematic review and meta-analysis to investigate the association of proposed macrophage markers with prognosis across epithelial tumors and melanoma. The Medline search engine was used and 195 articles were recovered for full review. Only articles which measured markers using immunohistochemistry or immunofluorescence and had overall survival (OS) as the primary endpoint were included. One hundred and thirteen articles were finally accepted for analysis. CD68 was associated with worse survival across tumors (hazard ratio (HR) = 1.24, 95% CI = 1.11-1.37). Tumor anatomical location influenced this association. Colorectal tumors showed an inverse association between CD68 and OS in contrast to the rest of cancer types (HR = 0.56 vs. 1.34). The approach taken to measure CD68 had an impact on prognosis; when macrophages were measured at the tumor invasion front prognosis was more favorable than when they were measured intratumorally (HR = 0.94 vs. 1.4). CD163, CD204, and CD206 showed a robust association with worse OS (HR = 1.63, 1.95, 1.65, respectively). Tumors arising in the lung and the liver showed a weaker association between CD163 and OS as compared with other locations (beta = -0.5401 for the lung and -0.5940 for the liver compared with other anatomical locations). The counting strategy also had an impact on CD163 association with OS, with hot-spot counting having higher HRs compared with averaging macrophage counts across spots or absolute cell counting (beta = -0.4678). In conclusion, proposed M2 markers are associated with worse survival across epithelial tumors and melanoma. The anatomical origin of tumors influences this association. The compartment where the macrophages were scored and counting strategy influenced the association with OS of CD68 and CD163, respectively.
  • Autores: Mielgo-Rubio, X.; Calvo, V.; Luna, J.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.12 N° 11 2020 págs. 3459
    Resumen
    Simple Summary In recent years there has been a trend towards an increase in the proportion of non-small cell lung cancer patients diagnosed with localized stage instead of advanced. However, 5-year survival rates continue to be low, even among patients diagnosed at early stages. In recent years major advances have been made in the treatment of advanced NSCLC, in large part due to the irruption of immunotherapy. PD-1 axis blocking-based immunotherapy is already a well-established standard of care treatment for patients with advances NSCLC, in frontline setting and in pretreated patients. Our greatest challenge now is to move the benefit of immunotherapy to patients with early-stage NSCLC so as to increase 5-year survival rate. The aim of this manuscript is to make a comprehensive review of available evidence, make a critical review of the results of published and ongoing studies, and analyze the role of biomarkers, main areas of controversy and future challenges. Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options.
  • Autores: Rodríguez Ruiz, María Esperanza; Yamazaki, T. ; Buque, A.; et al.
    Revista: METHODS IN ENZYMOLOGY
    ISSN: 0076-6879 Vol.635 2020 págs. 111 - 125
    Resumen
    Focal radiation therapy has the potential to generate systemic tumor-targeting immune responses so potent as to eradicate anatomically distant, non-irradiated malignant lesions, a phenomenon commonly referred to as "the abscopal response." In cancer patients, bona fide abscopal responses are rare, although the recent introduction of immune checkpoint blockers into the clinical practice has significantly increased their incidence. In rodents, abscopal responses can be conveniently modeled by establishing two, slightly asynchronous and anatomically distant subcutaneous tumors in syngeneic immunocompetent hosts, provided that the therapeutic partners of radiation potentially included in the regimen of choice do not mediate systemic anticancer effects per se. Here, we describe such method to monitor abscopal responses based on mammary carcinoma TSA cells implanted in syngeneic immunocompetent BALB/c mice. With minor variations, the same technique can be conveniently applied to a variety of transplantable mouse tumors.
  • Autores: Alvarez Rodriguez, Maite; Ochoa Nieto, Maria del Carmen; Minute, L.; et al.
    Revista: METHODS IN ENZYMOLOGY
    ISSN: 0076-6879 Vol.631 2020 págs. 257-275
    Resumen
    Natural killer (NK) cells have shown to play a critical, but as yet poorly defined, role in the process by which the immune system controls tumor progression. Indeed, NK cell-based immunotherapy, particularly NK cell adoptive transfer therapy, has become a very attractive cancer weapon against multiple types of cancers such as metastatic and hematological cancers. Unfortunately, the implementation of these therapies has been challenged by the existence of immunosuppression mechanisms that have prevented NK cell functionality. Additionally, the development of protocols to obtain purified and functional NK cells has faced some difficulties due to the limitations in the numbers of cells that can be obtained and the development of an exhaustion phenotype with impaired proliferative and functional capabilities during lengthy ex vivo NK cell expansion protocols. Thus, the development of new strategies to obtain a rapid expansion of highly functional NK cells without the appearance of exhaustion is still much needed. This is particularly true in the case of mouse NK cells, a surrogate commonly used to evaluate NK cell biology and human NK cell-based immunotherapeutic alternatives. Here, we describe a feasible and rapid protocol to produce strongly activated mouse NK cells in vivo taking advantage of the hydrodynamic delivery of a plasmid that contains interleukin-15, a cytokine known to cause NK cell expansion and activation, fused with the binding domain of the IL-15R alpha ("sushi
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Awada, A.; Calvo, E.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.5 N° 3 2020 págs. e000662
    Resumen
    During the last years, there has been a dramatic increase in the administrative and bureaucratic burden associated with clinical research, which has clearly had an impact on its overall efficiency and on the activity of clinical investigators and research teams. Indeed, the supervision of the adherence of clinical research to Good Clinical Practice (GCP) guidelines and legal regulations is of the utmost importance. Yet, while such regulations have remained largely unchanged during recent years, the number of administrative tasks and their complexity have grown markedly, as supported by the results of a survey performed among 940 clinical investigators that we report in this manuscript. Therefore, many investigators believe that it has become necessary to undertake a rigorous analysis of the causes and consequences of this issue, and to create a conduit to channel the advice from experienced investigators regarding clinical research procedures, in order to improve them. Based on these premises, ESMO has launched the ESMO Clinical Research Observatory (ECRO), a task force that will analyse different aspects of clinical research. ECRO will aim to provide the views of ESMO on clinical research procedures based on the feedback from clinical investigators, under complete adherence to the Declaration of Helsinki, the GCP guidelines and any other applicable legal regulations, while at the same time showing profound respect for all the stakeholders involved in clinical research. This
  • Autores: Wischhusen, J. (Autor de correspondencia); Melero Bermejo, Ignacio; Fridman, W. H.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.11 2020 págs. 951
    Resumen
    Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor beta superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor alpha-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.
  • Autores: Wculek, S. K.; Cueto, F. J.; Mujal, A. M.; et al.
    Revista: NATURE REVIEWS IMMUNOLOGY
    ISSN: 1474-1733 Vol.20 N° 1 2020 págs. 7 - 24
    Resumen
    Dendritic cells (DCs) are a diverse group of specialized antigen-presenting cells with key roles in the initiation and regulation of innate and adaptive immune responses. As such, there is currently much interest in modulating DC function to improve cancer immunotherapy. Many strategies have been developed to target DCs in cancer, such as the administration of antigens with immunomodulators that mobilize and activate endogenous DCs, as well as the generation of DC-based vaccines. A better understanding of the diversity and functions of DC subsets and of how these are shaped by the tumour microenvironment could lead to improved therapies for cancer. Here we will outline how different DC subsets influence immunity and tolerance in cancer settings and discuss the implications for both established cancer treatments and novel immunotherapy strategies. There is growing interest in harnessing dendritic cells for cancer immunotherapy. Here the authors describe the roles of dendritic cells in the tumour microenvironment and the different strategies that are being developed to target these cells in the clinic.
  • Autores: Fernandez-Sendin, M.; Tenesaca Cayambe, Shirley; Vasquez, M. ; et al.
    Revista: METHODS IN ENZYMOLOGY
    ISSN: 0076-6879 Vol.635 2020 págs. 185 - 203
    Resumen
    Recombinant adeno-associated viruses (rAAVs) are attractive tools for research in cancer immunotherapy. A single administration of an AAV vector in tumor mouse models induces a progressive increase in transgene expression which reaches a plateau 1 or 2 weeks after administration. The rAAV is then able to maintain the expression of the immunostimulatory transgene. Thus, the use of these vectors obviates the need for frequent administrations of the therapeutic protein to achieve the antitumor effect. The long-term expression of AAV vectors can be exploited for the evaluation of the antitumor activity of immune-enhancing proteins. Most preclinical studies have focused on the expression of cytokines and on the induction of immune responses elicited by tumor-associated antigens expressed by rAAVs. Notwithstanding, rAAVs may not be suitable for immunostimulatory proteins that require high and/or immediate expression. In this chapter, we review a feasible, reliable and detailed protocol to produce and purify AAV vectors as a tool for cancer immunotherapy strategies.
  • Autores: Cirella, A.; Berraondo López, Pedro; Di Trani, C. A .; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.26 N° 23 2020 págs. 6080 - 6082
    Resumen
    IL12 is a very potent cancer immunotherapy agent, but is difficult to harness safely if given systemically. Local gene transfer aims to confine the effects of IL12 to malignant tissues, thus avoiding toxicity. Lipid-nanoparticle mRNA achieves IL12 expression and efficacy in mouse models, opening the way to an ongoing trial.
  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Alvarez Rodriguez, Maite; Minute, L.; et al.
    Revista: TRENDS IN CANCER
    ISSN: 2405-8025 Vol.6 N° 3 2020 págs. 173 - 174
    Resumen
    Recent investigations (Rodriguez-Ruiz et al.) have established the counterintuitive idea that delaying apoptosis upon tumor irradiation by caspase 3 inhibition in tumor cells raises the immunogenicity of dying malignant cells.
  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Gato Cañas, María; Shekarian, T.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 N° 1 2020 págs. e000443
    Resumen
    Intratumoral delivery of viruses and virus-associated molecular patterns can achieve antitumor effects that are largely mediated by the elicitation or potentiation of immune responses against the malignancy. Attenuated vaccines are approved and marketed as good manufactiring practice (GMP)-manufactured agents whose administration might be able to induce such effects. Recent reports in mouse transplantable tumor models indicate that the rotavirus, influenza and yellow fever vaccines can be especially suitable to elicit powerful antitumor immunity against cancer following intratumoral administration. These results highlight that intratumoral anti-infectious vaccines can turn cold tumors into hot, and underscore the key role played by virus-induced type I interferon pathways to overcome resistance to immune checkpoint-targeted antibodies.
  • Autores: Melero Bermejo, Ignacio (Autor de correspondencia); Berraondo López, Pedro
    Revista: JOURNAL OF EXPERIMENTAL MEDICINE
    ISSN: 0022-1007 Vol.217 N° 12 2020
    Resumen
    4-1BB (CD137, TNFRSF9) mediates costimulatory signals important for activation and persistence of cytotoxic T lymphocytes. In this issue of JEM, Oda et al. (https://doi.org/10.1084/jem.20191166) report on a chimeric construction encompassing extracellular Fas and intracellular 4-1BB to dramatically improve adoptive T cell therapy.
  • Autores: Olivera, I. ; Etxeberria Uriz, Iñaki; Bolaños Mateo, Elixabet; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.26 N° 6 2020 págs. 1203 - 1204
    Resumen
    T-cell recognizable p53 hotspot mutations offer opportunities for immunotherapy and immune monitoring. Recognition of p53 mutations by peripheral blood CD8 and CD4 T lymphocytes has been revealed.
  • Autores: Alvarez Rodriguez, Maite (Autor de correspondencia); Simonetta, F.; Baker, J. ; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.11 2020
    Resumen
    The induction of exhaustion on effector immune cells is an important limiting factor for cancer immunotherapy efficacy as these cells undergo a hierarchical loss of proliferation and cytolytic activity due to chronic stimulation. Targeting PD-1 has shown unprecedented clinical benefits for many cancers, which have been attributed to the prevention of immune suppression and exhaustion with enhanced anti-tumor responses. In this study, we sought to evaluate the role of the PD-1/PD-L1 pathway in murine natural killer (NK) cell activation, function, and exhaustion. In an in vivo IL-2-dependent exhaustion mouse model, neutralization of the PD-1/PD-L1 pathway improved NK cell activation after chronic stimulation when compared to control-treated mice. These cells displayed higher proliferative capabilities and enhanced granzyme B production. However, the blockade of these molecules during long-term in vitro IL-2 stimulation did not alter the progression of NK cell exhaustion (NCE), suggesting an indirect involvement of PD-1/PD-L1 on NCE. Given the expansion of CD8 T cells and regulatory T cells (Tregs) observed upon acute and chronic stimulation with IL-2, either of these two populations could influence NK cell homeostasis after PD-L1/PD-1 therapy. Importantly, CD8 T cell activation and functional phenotype were indeed enhanced by PD-1/PD-L1 therapy, particularly with anti-PD-1 treatment that resulted in the highest upregulation of CD25 during chronic stimulation and granted an advantage for IL-2 over NK cells. These results indicate a competition for resources between NK and CD8 T cells that arguably delays the onset of NCE rather than improving its activation during chronic stimulation. Supporting this notion, the depletion of CD8 T cells reversed the benefits of PD-1 therapy on chronically stimulated NK cells. These data suggest a bystander effect of anti-PD1 on NK cells, resulting from the global competition that exists between NK and CD8 T cells for IL-2 as a key regulator of these cells' activation. Thus, achieving an equilibrium between these immune cells might be important to accomplish long-term efficacy during anti-PD-1/IL-2 therapy.
  • Autores: Otano Andrés, Itziar (Autor de correspondencia); Alvarez Rodriguez, Maite; Minute, L.; et al.
    Revista: THERANOSTICS
    ISSN: 1838-7640 Vol.10 N° 10 2020 págs. 4481 - 4489
    Resumen
    Activation-induced cell death (AICD) is a complex immunoregulatory mechanism that causes the demise of a fraction of T-lymphocytes upon antigen-driven activation. In the present study we investigated the direct role of TNF in AICD of CD8 T lymphocytes. Methods: Human peripheral mononuclear cells were isolated from healthy donors and fresh tumor-infiltrating lymphocytes were obtained from cancer patients undergoing surgery. T cells were activated with anti-CD3/CD28 mAbs or with a pool of virus peptides, in combination with clinical-grade TNF blocking agents. Results: A portion of CD8 T cells undergoes apoptosis upon CD3/CD28 activation in a manner that is partially prevented by the clinically used anti-TNF agents infliximab and etanercept. TNF-mediated AICD was also observed upon activation of virus-specific CD8 T cells and tumor-infiltrating CD8 T lymphocytes. The mechanism of TNF-driven T cell death involves TNFR2 and production of mitochondrial oxygen free radicals which damage DNA. Conclusion: The use of TNF blocking agents reduces oxidative stress, hyperpolarization of mitochondria, and the generation of DNA damage in CD8 T celss undergoing activation. The fact that TNF mediates AICD in human tumor-reactive CD8 T cells suggests that the use of TNF-blocking agents can be exploited in immunotherapy strategies.
  • Autores: Marquez-Rodas, I. (Autor de correspondencia); Longo, F. ; Rodríguez Ruiz, María Esperanza; et al.
    Revista: SCIENCE TRANSLATIONAL MEDICINE
    ISSN: 1946-6234 Vol.12 N° 565 2020
    Resumen
    Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.
  • Autores: Herbst, R. S. (Autor de correspondencia); Garon, E. B.; Kim, D. W.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.38 N° 14 2020 págs. 1580 - 1590
    Resumen
    Purpose: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in previously treated, programmed death-ligand 1 (PD-L1)¿expressing advanced non¿small-cell lung cancer (NSCLC) in patients with a tumor proportion score (TPS) ¿ 50% and ¿ 1%. We report KEYNOTE-010 long-term outcomes, including after 35 cycles/2 years or second-course pembrolizumab. Methods: Of 1,033 patients randomly assigned (intention to treat), 690 received up to 35 cycles/2 years of pembrolizumab 2 mg/kg (n = 344) or 10 mg/kg (n = 346) every 3 weeks, and 343 received docetaxel 75 mg/m2 every 3 weeks. Eligible patients with disease progression after 35 cycles/2 years of pembrolizumab could receive second-course treatment (up to 17 cycles). Pembrolizumab doses were pooled because no between-dose difference was observed at primary analysis. Results: Pembrolizumab continued to improve OS over docetaxel in the PD-L1 TPS ¿ 50% and ¿ 1% groups (hazard ratio [HR], 0.53; 95% CI, 0.42 to 0.66; P < .00001; and HR, 0.69; 95% CI, 0.60 to 0.80; P < .00001, respectively) after a 42.6-month (range, 35.2-53.2 months) median follow-up. Estimated 36-month OS rates were 34.5% versus 12.7% and 22.9% versus 11.0%, respectively. Grade 3-5 treatment-related adverse events occurred in 16% versus 37% of patients, respectively. Seventy-nine of 690 patients completed 35 cycles/2 years of pembrolizumab; 12-month OS and progression-free survival rates after completing treatment were 98.7% (95% CI, 91.1% to 99.8%) and 72.5% (95% CI, 59.9% to 81.8%), respectively. Seventy-five patients (95%) had objective response (RECIST v1.1, blinded independent central review) and 48 (64%) had ongoing response. Grade 3-5 treatment-related adverse events occurred in 17.7% of patients. Fourteen patients received second-course pembrolizumab: 5 completed 17 cycles, 6 (43%) had partial response, and 5 (36%) had stable disease. Conclusion: Pembrolizumab provided long-term OS benefit over docetaxel, with manageable safety, durable responses among patients receiving 2 years of treatment, and disease control with second-course treatment, further supporting pembrolizumab for previously treated, PD-L1¿expressing advanced NSCLC. Trial registration: ClinicalTrials.gov NCT01905657.
  • Autores: Mastelic-Gavillet, B.; Sarivalasis, A.; Lozano, L. E.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.135 2020 págs. 173 - 182
    Resumen
    Background: Dendritic cells (DCs) are the most efficient antigen-presenting cells, hence initiating a potent and cancer-specific immune response. This ability (mainly using monocyte-derived DCs) has been exploited in vaccination strategies for decades with limited clinical efficacy. Another alternative would be the use of conventional DCs (cDCs) of which at least three subsets circulate in human blood: cDC1s (CD141(bright)), cDC2s (CD1c(+)) and plasmacytoid DCs. Despite their paucity, technical advances may allow for their selection and clinical use. However, many assumptions concerning the DC subset biology depend on observations from mouse models, hindering their translational potential. In this study, we characterise human DCs in patients with ovarian cancer (OvC) or prostate cancer (PrC). Patients and methods: Whole blood samples from patients with OvC or PrC and healthy donors (HDs) were evaluated by flow cytometry for the phenotypic and functional characterisation of DC subsets. Results: In both patient groups, the frequency of total CD141(+) DCs was lower than that in HDs, but the cDC1 subset was only reduced in patients with OvC. CD141(+) DCs showed a reduced response to the TLR3 agonist poly (I:C) in both groups of patients. An inverse correlation between the frequency of cDC1s and CA125, the OvC tumour burden marker, was observed. Consistently, high expression of CLEC9A in OvC tissue (The Cancer Genome Atlas data set) indicated a better overall survival. Conclusions: cDC1s are reduced in patients with OvC, and CD141(+) DCs are quantitatively and qualitatively impaired in patients with OvC or PrC. CD141(+) DC activation may predict functional impairment. The loss of cDC1s may be a bad prognostic factor for patients with OvC.
  • Autores: Teijeira Sánchez, Álvaro (Autor de correspondencia); Garasa, S.; Gato Cañas, María; et al.
    Revista: IMMUNITY
    ISSN: 1074-7613 Vol.52 N° 5 2020 págs. 856 - 871.E8
    Resumen
    Neutrophils are expanded and abundant in cancer-bearing hosts. Under the influence of CXCR1 and CXCR2 chemokine receptor agonists and other chemotactic factors produced by tumors, neutrophils, and granulocytic myeloid-derived suppressor cells (MDSCs) from cancer patients extrude their neutrophil extracellular traps (NETs). In our hands, CXCR1 and CXCR2 agonists proved to be the major mediators of cancer-promoted NETosis. NETs wrap and coat tumor cells and shield them from cytotoxicity, as mediated by CD8+ T cells and natural killer (NK) cells, by obstructing contact between immune cells and the surrounding target cells. Tumor cells protected from cytotoxicity by NETs underlie successful cancer metastases in mice and the immunotherapeutic synergy of protein arginine deiminase 4 (PAD4) inhibitors, which curtail NETosis with immune checkpoint inhibitors. Intravital microscopy provides evidence of neutrophil NETs interfering cytolytic cytotoxic T lymphocytes (CTLs) and NK cell contacts with tumor cells.
  • Autores: Schalper, K. A. (Autor de correspondencia); Carleton, M. ; Zhou, M. ; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.26 N° 5 2020 págs. 688 - 692
    Resumen
    Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.
  • Autores: Minute, L. ; Teijeira Sánchez, Álvaro; Sanchez-Paulete, A. R. ; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 N° 1 2020 págs. e000325
    Resumen
    Background The immune response to cancer is often conceptualized with the cancer immunity cycle. An essential step in this interpretation is that antigens released by dying tumors are presented by dendritic cells to naive or memory T cells in the tumor-draining lymph nodes. Whether tumor cell death resulting from cytotoxicity, as mediated by T cells or natural killer (NK) lymphocytes, is actually immunogenic currently remains unknown. Methods In this study, tumor cells were killed by antigen-specific T-cell receptor (TCR) transgenic CD8 T cells or activated NK cells. Immunogenic cell death was studied analyzing the membrane exposure of calreticulin and the release of high mobility group box 1 (HMGB1) by the dying tumor cells. Furthermore, the potential immunogenicity of the tumor cell debris was evaluated in immunocompetent mice challenged with an unrelated tumor sharing only one tumor-associated antigen and by class I major histocompatibility complex (MHC)-multimer stainings. Mice deficient in Batf3, Ifnar1 and Sting1 were used to study mechanistic requirements. Results We observe in cocultures of tumor cells and effector cytotoxic cells, the presence of markers of immunogenic cell death such as calreticulin exposure and soluble HMGB1 protein. Ovalbumin (OVA)-transfected MC38 colon cancer cells, exogenously pulsed to present the gp100 epitope are killed in culture by mouse gp100-specific TCR transgenic CD8 T cells. Immunization of mice with the resulting destroyed cells induces epitope spreading as observed by detection of OVA-specific T cells by MHC multimer staining and rejection of OVA(+) EG7 lymphoma cells. Similar results were observed in mice immunized with cell debris generated by NK-cell mediated cytotoxicity. Mice deficient in Batf3-dependent dendritic cells (conventional dendritic cells type 1, cDC1) fail to develop an anti-OVA response when immunized with tumor cells killed by cytotoxic lymphocytes. In line with this, cultured cDC1 dendritic cells uptake and can readily cross-present antigen from cytotoxicity-killed tumor cells to cognate CD8(+) T lymphocytes. Conclusion These results support that an ongoing cytotoxic antitumor immune response can lead to immunogenic tumor cell death.
  • Autores: Aznar Gómez, María Ángela (Autor de correspondencia); Molina, C. ; Teijeira Sánchez, Álvaro; et al.
    Revista: EMBO MOLECULAR MEDICINE
    ISSN: 1757-4676 Vol.12 N° 1 2020 págs. e10375
    Resumen
    Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild-type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non-transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T-cell-dependent manner. In mice bearing bilateral tumors in which only one is intratumorally injected, contralateral therapeutic effects are observed consistent with more prominent CD8 T-cell infiltrates and a treatment-related reduction of Tregs. Additive efficacy effects were observed upon co-treatment with intratumoral 17D and systemic anti-CD137 and anti-PD-1 immunostimulatory monoclonal antibodies. Importantly, when mice were preimmunized with 17D, intratumoral 17D treatment achieved better local and distant antitumor immunity. Such beneficial effects of prevaccination are in part explained by the potentiation of CD4 and CD8 T-cell infiltration in the treated tumor. The repurposed use of a GMP-grade vaccine to be given via the intratumoral route in prevaccinated patients constitutes a clinically feasible and safe immunotherapy approach.
  • Autores: De Andrea, Carlos Eduardo; Pérez Gracia, José Luis; Castañón Álvarez, Eduardo; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.9 N° 1 2020 págs. e1760676
    Resumen
    Checkpoint inhibitors have improved the survival of patients with advanced tumors and show a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery, external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade 1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient experienced a major partial response and, following the resolution of diarrhea, she was re-challenged again with
  • Autores: Tenesaca Cayambe, Shirley; Vásquez Durán, Marcos Antonio; Fernández-Sendin, M.; et al.
    Revista: MOLECULAR NUTRITION AND FOOD RESEARCH
    ISSN: 1613-4125 Vol.64 N° 15 2020 págs. 1901213
    Resumen
    Scope Vitamin D(3)is a critical molecule for the properly controlled activity of the immune system. In myeloid-derived cells, vitamin D(3)induces the production of the antimicrobial and antitumor peptide cathelicidin. In this study, the mechanism of the entry of 25-hydroxycholecalciferol (25(OH)D) in myeloid-derived cells is explored. Methods and results Here, a novel regulatory pathway of vitamin D(3)biology is described. Using a polyclonal antibody, two different chemical inhibitors, and a high-density lipoprotein as a competing ligand, it is demonstrated here that the 25(OH)D signaling pathway in myeloid cells depends on scavenger receptor class B type I (SR-B1). This effect is observed in the THP-1 monocytic cell line and in human primary monocytes. SR-B1 blockade abrogates the cellular uptake of 25(OH)D leading to a general shut down of the gene transcription program modulated by 25(OH)D. The results obtained at the transcriptional level are confirmed at the protein and functional level for CD14 in the THP-1 cell line. Conclusion In conclusion, SR-B1 plays a critical role in vitamin D(3)biology, paving the way for novel therapeutic interventions.
  • Autores: Molins, J. B. ; Jimenez, J. G. D.; Valderrama, B. P.; et al.
    Revista: CLINICAL GENITOURINARY CANCER
    ISSN: 1558-7673 Vol.18 N° 6 2020 págs. 452 - 460
    Resumen
    Current first-line treatment for advanced urothelial carcinoma has a limited duration of response. The MAJA study aimed to compare vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in 88 patients after first-line treatment with cisplatin/gemcitabine. Results demonstrated a progression-free survival benefit and a positive OS trend (with limited power due to the small sample size) with VFL in maintenance therapy with no unexpected long-term adverse effects. Introduction: The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses. Patients and Methods: Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression. Results: At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL thorn BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P=.182). Post hoc group division did not affect median OS in either study arm. Conclusion: Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage. (C) 2020 Elsevier Inc. All rights reserved.
  • Autores: Davar, D.; Simonelli, M. ; Gutierrez, M. ; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 2020 págs. A239 - A240
  • Autores: Ascierto, P. A.; Mandala, M.; Ferrucci, P. F. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.31 2020 págs. S1173 - S1174
  • Autores: Moreno, V. ; Hernandez, T. ; Melero Bermejo, Ignacio; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 2020 págs. A225 - A226
  • Autores: Bedke, J.; Merseburger, A. S.; Loriot, Y.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.38 N° 6 2020
  • Autores: Melero Bermejo, Ignacio; Fernández de Sanmamed Gutiérrez, Miguel; Calvo, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.31 2020 págs. S707 - S707
  • Autores: Rodriguez-Moreno, J. F.; de Velasco, G.; Fernandez, I. B.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.38 N° 6 2020 págs. S542
  • Autores: Bastidas Tamayo, Juan Fernando; Grisanti Vollbracht, Fabiana Lucrecia; Rosales Castillo, Juan Jose; et al.
    Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
    ISSN: 1619-7070 Vol.47 N° SUPPL 1 2020 págs. S325 - S326
  • Autores: Garralda, E. ; Geva, R.; Ben-Ami, E. ; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 2020 págs. A250 - A251
  • Autores: Pérez Gracia, José Luis; Andueza Arrieta, María Pilar; Patiño García, Ana; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.8 2020 págs. A44 - A44
  • Autores: Valderrama, B. P.; Gauna, D. C.; Marin, A. P. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.31 2020 págs. S1158 - S1159
  • Autores: Bendell, J. C.; Bedard, P. ; Bang, Y. J. ; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.80 N° 16 2020
  • Autores: Rodríguez Ruiz, María Esperanza (Autor de correspondencia); Rodriguez, I.; Leaman, O.; et al.
    Revista: PHARMACOLOGY AND THERAPEUTICS
    ISSN: 0163-7258 Vol.196 2019 págs. 195 - 203
    Resumen
    Radiotherapy of cancer has been traditionally considered as a local therapy without noticeable effects outside the irradiated fields. However, ionizing radiation exerts multiple biological effects on both malignant and stromal cells that account for a complex spectrum of mechanisms beyond simple termination of cancer cells. In the era of immunotherapy, interest in radiation-induced inflammation and cell death has considerably risen, since these mechanisms lead to profound changes in the systemic immune response against cancer antigens. Immunotherapies such as immunomodulatory monoclonal antibodies (anti-PD-1, anti-CTLA-4, anti-CD137, anti-OX40, anti-CD40, anti-TGF beta), TLR-agonists, and adoptive T-cell therapy have been synergistically combined with radiotherapy in mouse models. Importantly, radiation and immunotherapy combinations do not only act against the irradiated tumor but also against distant non-irradiated metastases (abscopal effects). A series of clinical trials are exploring the beneficial effects of radioimmunotherapy combinations. The concepts of crosspriming of tumor neoantigens and immunogenic cell death are key elements underlying this combination efficacy. Proinflamatory changes in the vasculature of the irradiated lesions and in the cellular composition of the leukocyte infiltrates in the tumor microenvironment contribute to raise or dampen cancer immunogenicity. It should be stressed that not all effects of radiotherapy favor antitumor immunity as there are counterbalancing mechanisms such as TGF beta, and VEGFs that inhibit the efficacy of the antitumor immune response, hence offering additional therapeutic targets to suppress. All in all, radiotherapy and immunotherapy are compatible and often synergistic approaches against cancer that jointly target irradiated and non-irradiated malignant lesions in the same patient. (C) 2018 Published by Elsevier Inc.
  • Autores: Alcibar, O. L. (Autor de correspondencia); Candini, D.; Lopez-Campos, F.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.21 N° 8 2019 págs. 992 - 1004
    Resumen
    Harnessing the patient's own immune system against an established cancer has proven to be a successful strategy. Within the last years, several antibodies blocking critical checkpoints that control the activation of T cells, the immune cells able to kill cancer cells, have been approved for the use in patients with different tumours. Unfortunately, these cases remain a minority. Over the last years, radiotherapy has been reported as a means to turn a patient's own tumour into an in situ vaccine and generate anti-tumour T cells in patients who lack sufficient anti-tumour immunity. Indeed, review data show that the strategy of blocking multiple selected immune inhibitory targets in combination with radiotherapy has the potential to unleash powerful anti-tumour responses and improve the outcome of metastatic solid tumours. Here, we review the principal tumours where research in this field has led to new knowledge and where radioimmunotherapy becomes a reality.
  • Autores: Etxeberria Uriz, Iñaki (Autor de correspondencia); Gonzalez Vaz, Javier; Teijeira Sánchez, Álvaro; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.4 N° Supl. 3 2019 págs. e000733
    Resumen
    CD137 (4-1BB) is a surface glycoprotein that belongs to the tumour necrosis factor receptor family (TNFRSF9). Its expression is induced on activation on a number of leucocyte types. Interestingly, for cancer immunotherapy, CD137 becomes expressed on primed T and natural killer (NK) cells, which on ligation provides powerful costimulatory signals. Perturbation of CD137 by CD137L or agonist monoclonal antibodies on activated CD8 T cells protects such antigen-specific cytotoxic T lymphocytes from apoptosis, enhances effector functionalities and favours persistence and memory differentiation. As a consequence, agonist antibodies exert potent antitumour effects in mouse models and the CD137 signalling domain is critical in chimeric antigen receptors (CAR) of CAR T cells approved to be used in the clinic. New formats of CD137 agonist moieties are being clinically developed, seeking potent costimulation targeted to the tumour microenvironment to avoid liver inflammation side effects, that have thus far limited and delayed clinical development.
  • Autores: Baraibar Argota, Iosune; Melero Bermejo, Ignacio; Ponz Sarvisé, Mariano; et al.
    Revista: DRUG SAFETY
    ISSN: 0114-5916 Vol.42 N° 2 2019 págs. 281 - 294
    Resumen
    Immunotherapy has emerged in recent years and has revolutionized the treatment of cancer. Immune checkpoint inhibitors, including anti-cytotoxic T lymphocyte antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) agents, are the first of this new generation of treatments. Anti-PD-1/PD-L1 agents target immune cells by blocking the PD-1/PD-L1 pathway. This blockade leads to enhancement of the immune system and therefore restores the tumour-induced immune deficiency selectively in the tumour microenvironment. However, this shift in the balance of the immune system can also produce adverse effects that involve multiple organs. The pattern of toxicity is different from traditional chemotherapy agents or targeted therapy, and there is still little experience in recognizing and managing it. Thus, toxicity constitutes a real clinical management challenge and any new alteration should be suspected of being treatment-related. The most common toxicities occur in the skin, gastrointestinal tract, lungs, and endocrine, musculoskeletal, renal, nervous, haematologic, cardiovascular and ocular systems. Immune-mediated toxic effects are usually manageable, but toxicities may sometimes lead to treatment withdrawal, and even fulminant and fatal events can occur. Oncologists need to collaborate with internists, clinical immunologists and other specialists to understand, manage and prevent toxicity derived from immunotherapy. This review focuses on the mechanisms of toxicity of anti-PD-1/PD-L1 agents, and its diagnosis and management.
  • Autores: Bol, K. F. (Autor de correspondencia); Schreibelt, G.; Rabold, K.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.7 2019
    Resumen
    Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141(+) and CD1c(+) myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c(+) myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c(+) myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c(+) myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141(+) myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy.
  • Autores: Berraondo López, Pedro (Autor de correspondencia); Fernández de Sanmamed Gutiérrez, Miguel; Ochoa Nieto, Maria del Carmen; et al.
    Revista: BRITISH JOURNAL OF CANCER
    ISSN: 0007-0920 Vol.120 N° 1 2019 págs. 6 - 15
    Resumen
    Cytokines are soluble proteins that mediate cell-to-cell communication. Based on the discovery of the potent anti-tumour activities of several pro-inflammatory cytokines in animal models, clinical research led to the approval of recombinant interferon-alpha and interleukin-2 for the treatment of several malignancies, even if efficacy was only modest. These early milestones in immunotherapy have been followed by the recent addition to clinical practice of antibodies that inhibit immune checkpoints, as well as chimeric antigen receptor T cells. A renewed interest in the anti-tumour properties of cytokines has led to an exponential increase in the number of clinical trials that explore the safety and efficacy of cytokine-based drugs, not only as single agents, but also in combination with other immunomodulatory drugs. These second-generation drugs under clinical development include known molecules with novel mechanisms of action, new targets, and fusion proteins that increase half-life and target cytokine activity to the tumour microenvironment or to the desired effector immune cells. In addition, the detrimental activity of immunosuppressive cytokines can be blocked by antagonistic antibodies, small molecules, cytokine traps or siRNAs. In this review, we provide an overview of the novel trends in the cytokine immunotherapy field that are yielding therapeutic agents for clinical trials.
  • Autores: Doroshow, D. B.; Fernández de Sanmamed Gutiérrez, Miguel; Hastings, K.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 15 2019 págs. 4592 - 4602
    Resumen
    Immune-checkpoint inhibitors (ICI), particularly inhibitors of the PD-1 axis, have altered the management of non-small cell lung cancer (NSCLC) over the last 10 years. First demonstrated to improve outcomes in second-line or later therapy of advanced disease, ICIs were shown to improve overall survival compared with chemotherapy in first-line therapy for patients whose tumors express PD-L1 on at least 50% of cells. More recently, combining ICIs with chemotherapy has been shown to improve survival in patients with both squamous and nonsquamous NSCLC, regardless of PD-L1 expression. However, PD-L1 and, more recently, tumor mutational burden have not proven to be straightforward indicative biomarkers. We describe the advances to date in utilizing these biomarkers, as well as novel markers of tumor inflammation, to ascertain which patients are most likely to benefit from ICIs. Ongoing translational work promises to improve the proportion of patients who benefit from these agents.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Loriot, Y. ; Rosenberg, J. E.; et al.
    Revista: EUROPEAN UROLOGY
    ISSN: 0302-2838 Vol.75 N° 3 2019 págs. E82 - E83
  • Autores: Gallardo, E. ; Mendez-Vidal, M. J. ; Pérez Gracia, José Luis; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.21 N° 5 2019 págs. 692 - 693
  • Autores: Buque, A.; Rodríguez Ruiz, María Esperanza; Fucikova, J. ; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.8 N° 11 2019 págs. e1655364
    Resumen
    Caspases are known for their ability to precipitate apoptosis. Our findings indicate that accelerating the terminal inactivation of cells dying in response to radiation therapy limit their immunogenicity as a consequence of reduced type I interferon secretion. Thus, caspase inhibitors stand out as promising combinatorial partners to improve the immunogenicity of radiation therapy in the clinic.
  • Autores: Berraondo López, Pedro; Ochoa Nieto, Maria del Carmen; Olivera, Irene; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.9 N° 8 2019 págs. 1003 - 1005
    Resumen
    About one third of cases of hepatocellular carcinoma (HCC) show gain-of-function mutations of CTNNB1 (beta-catenin) that correlate with sparse intratumoral T-cell content, as observed previously in an ample spectrum of malignancies, and there is mounting preliminary evidence that such HCC cases are refractory to treatment with PD-1 checkpoint inhibitors. Elegant hepatocarcinogenesis experiments by in vivo gene transfer to mouse hepatocytes show that coexpression of active forms of beta-catenin result in poor T-cell infiltrates, faster progression in immunocompetent hosts, and unresponsiveness to immunotherapy with checkpoint inhibitors.
  • Autores: Salas Benito, Diego; Melero Bermejo, Ignacio; Ponz Sarvisé, Mariano (Autor de correspondencia)
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 18 2019 págs. 5435 - 5437
    Resumen
    No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes-based vaccine encoding for mesothelin in combination with a GM-CSF-transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients.
  • Autores: Marquez-Rodas, I. (Autor de correspondencia); Aznar Gómez, María Ángela; Calles, A.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 4 2019 págs. 1127 - 1129
    Resumen
    Intratumoral immunotherapy can potentially modulate the tumor microenvironment (TME) and potentiate the effects of concomitant or sequential systemic immunotherapies. Intratumoral administration of different Toll-like receptor agonists, including TLR4, can potentiate these effects through innate and adaptive immunity connection.
  • Autores: Fernández de Sanmamed Gutiérrez, Miguel; Etxeberria Uriz, Iñaki; Otano Andrés, Itziar; et al.
    Revista: SCIENCE TRANSLATIONAL MEDICINE
    ISSN: 1946-6234 Vol.11 N° 496 2019
  • Autores: Rodríguez Ruiz, María Esperanza; Buque, A. ; Hensler, M. ; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.8 N° 11 2019 págs. e1655964
    Resumen
    Caspase 3 (CASP3) has a key role in the execution of apoptosis, and many cancer cells are believed to disable CASP3 as a mechanism of resistance to cytotoxic therapeutics. Alongside, CASP3 regulates stress-responsive immunomodulatory pathways, including secretion of type I interferon (IFN). Here, we report that mouse mammary carcinoma TSA cells lacking Casp3 or subjected to chemical caspase inhibition were as sensitive to the cytostatic and cytotoxic effects of radiation therapy (RT) in vitro as their control counterparts, yet secreted increased levels of type I IFN. This effect originated from the accrued accumulation of irradiated cells with cytosolic DNA, likely reflecting the delayed breakdown of cells experiencing mitochondrial permeabilization in the absence of CASP3. Casp3(-/-) TSA cells growing in immunocompetent syngeneic mice were more sensitive to RT than their CASP3-proficient counterparts, and superior at generating bona fide abscopal responses in the presence of an immune checkpoint blocker. Finally, multiple genetic signatures of apoptotic proficiency were unexpectedly found to have robust negative (rather than positive) prognostic significance in a public cohort of breast cancer patients. However, these latter findings were not consistent with genetic signatures of defective type I IFN signaling, which were rather associated with improved prognosis. Differential gene expression analysis on patient subgroups with divergent prognosis (as stratified by independent signatures of apoptotic proficiency) identified SLC7A2 as a new biomarker with independent prognostic value in breast cancer patients. With the caveats associated with the retrospective investigation of heterogeneous, public databases, our data suggest that apoptotic caspases may influence the survival of breast cancer patients (or at least some subsets thereof) via mechanisms not necessarily related to type I IFN signaling as they identify a novel independent prognostic biomarker that awaits prospective validation.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Castellano, D. ; Climent, M. A.; et al.
    Revista: MEDICAL ONCOLOGY
    ISSN: 1357-0560 Vol.36 N° 3 2019 págs. 29
    Resumen
    The introduction of targeted therapy for the treatment of advanced renal cell carcinoma (RCC) has improved the outcome of these patients in the last decade. However, many patients still relapse. The aim of this consensus study was to establish common recommendations about the best treatment options in patients with RCC. A two-round Delphi methodology was used. A total of 25 statements were submitted to a panel of 30 specialists. If consensus was not obtained in the first round a second and last round was performed. Agreement was achieved for 19 of the proposed 25 statements (76%). When making a decision about the treatment option, considering the efficiency and response rate to previous treatment, drug's toxicity and the patients' clinical features are very relevant.
  • Autores: Perez-Ruiz, E.; Cordeiro Minute, Luna Ridan; Otano Andrés, Itziar; et al.
    Revista: NATURE
    ISSN: 0028-0836 Vol.569 N° 7756 2019 págs. 428 - 432
    Resumen
    Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer1-3. However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of ipilimumab that is given to patients4. In mice, co-treatment with surrogate anti-PD-1 and anti-CTLA-4 monoclonal antibodies is effective in transplantable cancer models, but also exacerbates autoimmune colitis. Here we show that treating mice with clinically available TNF inhibitors concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, improves anti-tumour efficacy. Notably, TNF is upregulated in the intestine of patients suffering from colitis after dual ipilimumab and nivolumab treatment. We created a model in which Rag2-/-Il2rg-/- mice were adoptively transferred with human peripheral blood mononuclear cells, causing graft-versus-host disease that was further exacerbated by ipilimumab and nivolumab treatment. When human colon cancer cells were xenografted into these mice, prophylactic blockade of human TNF improved colitis and hepatitis in xenografted mice, and moreover, immunotherapeutic control of xenografted tumours was retained. Our results provide clinically feasible strategies to dissociate efficacy and toxicity in the use of combined immune checkpoint blockade for cancer immunotherapy.
  • Autores: Etxeberria, I.; Bolaños, E.; Quetglas, J. I.; et al.
    Revista: CANCER CELL
    ISSN: 1535-6108 Vol.36 N° 6 2019 págs. 613 - 629
    Resumen
    Retroviral gene transfer of interleukin-12 (IL-12) into T cells markedly enhances antitumor efficacy upon adoptive transfer but has clinically shown unacceptable severe side effects. To overcome the toxicity, we engineered tumor-specific CD8+ T cells to transiently express IL-12. Engineered T cells injected intratumorally, but not intravenously, led to complete rejections not only of the injected lesion but also of distant concomitant tumors. Efficacy was further enhanced by co-injection with agonist anti-CD137 mAb or by transient co-expression of CD137 ligand. This treatment induced epitope spreading of the endogenous CD8+ T cell immune response in a manner dependent on cDC1 dendritic cells. Mouse and human tumor-infiltrating T lymphocyte cultures can be transiently IL-12 engineered to attain marked immunotherapeutic effects.
  • Autores: Hakenberg, O. W. (Autor de correspondencia); Pérez Gracia, José Luis; Castellano, D. ; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.107 2019 págs. 186 - 195
    Resumen
    Introduction: Platelet-derived growth factor receptor-alpha (PDGFR alpha) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFR alpha and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel. Methods: Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m(2), Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts. Results: A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87-1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72-1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade >= 3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043). Conclusions: Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered. (C) 2018 Published by Elsevier Ltd.
  • Autores: Wang, R.; Gao, C.; Raymond, M.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 22 2019 págs. 6709 - 6720
    Resumen
    Purpose: The success of checkpoint blockade has led to a significant increase in the development of a broad range of immunomodulatory molecules for the treatment of cancer, including agonists against T-cell costimulatory receptors, such as OX40. Unlike checkpoint blockade, where complete and sustained receptor saturation may be required for maximal activity, the optimal dosing regimen and receptor occupancy for agonist agents is less well understood and requires further study. Experimental Design: We integrated both preclinical and clinical biomarker data sets centered on dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic changes to model the optimal dose and schedule for the OX40 agonist antibody BMS-986178 alone and in combination with checkpoint blockade. Results: Administration of the ligand-blocking anti-mouse surrogate antibody OX40.23 or BMS-986178 as monotherapy or in combination with checkpoint blockade led to increased peripheral CD4(+) and CD8(+) T-cell activation in tumor-bearing mice and patients with solid tumors, respectively. OX40 receptor occupancy between 20% and 50% both in vitro and in vivo was associated with maximal enhancement of T-cell effector function by anti-OX40 treatment, whereas a receptor occupancy > 40% led to a profound loss in OX40 receptor expression, with clear implications for availability for repeat dosing. Conclusions: Our results highlight the value of an integrated translational approach applied during early clinical development to aggregate preclinical and clinical data in an effort to define the optimal dose and schedule for T-cell agonists in the clinic.
  • Autores: Berraondo López, Pedro (Autor de correspondencia)
    Revista: HEMASPHERE
    ISSN: 2572-9241 Vol.3 2019 págs. 28 - 30
    Resumen
    Take home messages Monoclonal antibodies targeting CTLA-4 enhance the activation of T lymphocytes. The toxicity of these monoclonal antibodies can be reduced targeting the antibody activity to the tumor microenvironment. Monoclonal antibodies targeting the PD-1/PD-L1 axis normalize the effector immune responses in the tumor microenvironment. These monoclonal antibodies are essential drugs for therapeutic combinations due to the excellent safety and efficacy profile of the PD-1/PD-L1 blockade.
  • Autores: Wculek, S. K.; Amores-Iniesta, J.; Conde-Garrosa, R. ; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.7 N° 1 2019 págs. 100
    Resumen
    Background: The manipulation of dendritic cells (DCs) for cancer vaccination has not reached its full potential, despite rile revolution in cancer immunotherapy. DCs are fundamental for CD8+ T cell activation, which relies on cross-presentation of exogenous antigen on MHC-I and can be fostered by immunogenic cancer cell death. Translational and clinical research has focused on in vitro-generated monocyte-derived DCs, while the vaccination efficacy of natural conventional type 1 DCs (cDC1s), which are associated with improved anti-tumor immunity and specialize on antigen cross-presentation, remains unknown. Methods: We isolated primary spleen mouse cDC1s and established a protocol for fast ex vivo activation and antigenloading with lysates of tumor cells that underwent immunogenic cell death by UV irradiation. Natural tumor antigen-loaded cDC1s were transferred and their potential for induction of endogenous CD8+ and CD4+ T cell responses in vivo, cancer prevention and therapy were assessed in three grafted cancer models. Further, we tested the efficacy of natural cDC1 vaccination in combination and comparison with anti-PD-1 treatment in two "wildtype" tumor models not expressing exogenous antigens. Results: Herein, we reveal that primary mouse cDC1s ex vivo loaded with dead tumor cell-derived antigen are activated and induce strong CD8+ T cell responses from the endogenous repertoire upon adoptive transfer in vivo through tumor antigen cross-presentation. Notably, cDC1-based vaccines enhance tumor infiltration by cancerreactive CD8+ and CD4+ T cells and halt progression of engrafted cancer models, including tumors that are refractory to anti-PD-1 treatment Moreover, combined tumor antigen-loaded primary cDC1 and anti-PD-1 therapy had strong synergistic effects in a PD-1 checkpoint inhibition susceptible cancer model. Conclusions: This preclinical proof-of-principle study is first to support the therapeutic efficacy of cancer immunotherapy with syngeneic dead tumor cell antigen-loaded mouse cDC1s, the equivalents of the human dendritic cell subset that correlates with beneficial prognosis of cancer patients. Our data pave the way for translation of cDC1-based cancer treatments into the clinic when isolation of natural human cDC1s becomes feasible.
  • Autores: Herbst, R. S. (Autor de correspondencia); Baas, P. ; Pérez Gracia, José Luis; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.30 N° 2 2019 págs. 281 - 289
    Resumen
    Background: In KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data. Patients and methods: PD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m2 Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) 50% and 1%; pembrolizumab doses were pooled in this analysis. Results: At date cut-off of 24 March 2017, median follow-up was 31 months (range 23-41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS 50%. For TPS 50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS 1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS 50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS 1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)]. Conclusion: Pembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.
  • Autores: Datar, I.; Fernández de Sanmamed Gutiérrez, Miguel; Wang, J.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.25 N° 15 2019 págs. 4663 - 4673
    Resumen
    Purpose: To determine the tumor tissue/cell distribution, functional associations, and clinical significance of PD-1, LAG3, and TIM-3 protein expression in human non-small cell lung cancer (NSCLC). Experimental Design: Using multiplexed quantitative immunofluorescence, we performed localized measurements of CD3, PD-1, LAG-3, and TIM-3 protein in > 800 clinically annotated NSCLCs from three independent cohorts represented in tissue microarrays. Associations between the marker's expression and major genomic alterations were studied in The Cancer Genome Atlas NSCLC dataset. Using mass cytometry (CyTOF) analysis of leukocytes collected from 20 resected NSCLCs, we determined the levels, coexpression, and functional profile of PD-1, LAG-3, and TIM-3 expressing immune cells. Finally, we measured the markers in baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers and known response to treatment. Results: PD-1, LAG-3, and TIM-3 were detected in tumorinfiltrating lymphocytes (TIL) from 55%, 41.5%, and 25.3% of NSCLC cases, respectively. These markers showed a prominent association with each other and limited association with major clinicopathologic variables and survival in patients not receiv-ing immunotherapy. Expression of the markers was lower in EGFR-mutated adenocarcinomas and displayed limited association with tumor mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T-cell subsets/NKT cells, whereas TIM-3 expression was higher in NK cells and macrophages. Coexpression of PD-1, LAG-3, and TIM-3 was associated with prominent T-cell activation (CD69/CD137), effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated levels of proapoptotic markers (FAS/BIM). LAG-3 and TIM-3 were present in TIL subsets lacking PD-1 expression and showed a distinct functional profile. In baseline samples from 90 patients with advanced NSCLC treated with PD-1 axis blockers, elevated LAG-3 was significantly associated with shorter progressionfree survival. Conclusions: PD-1, LAG-3, and TIM-3 have distinct tissue/cell distribution, functional implications, and genomic correlates in human NSCLC. Expression of these immune inhibitory receptors in TILs is associated with prominent activation, but also with a proapoptotic T-cell phenotype. Elevated LAG-3 expression is associated with insensitivity to PD-1 axis blockade, suggesting independence of these immune evasion pathways.
  • Autores: Ochoa Nieto, Maria del Carmen; Perez-Ruiz, E.; Minute, L. ; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.8 N° 7 2019 págs. 1599636
    Resumen
    Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38(+) tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFN gamma production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival.
  • Autores: Wang, J.; Fernández de Sanmamed Gutiérrez, Miguel; Datar, I.; et al.
    Revista: CELL
    ISSN: 0092-8674 Vol.176 N° 1 - 2 2019 págs. 334 - 347
    Resumen
    Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.
  • Autores: Teijeira Sánchez, Álvaro (Autor de correspondencia); Garasa, S.; Etxeberria Uriz, Iñaki; et al.
    Revista: CANCER IMMUNOLOGY RESEARCH
    ISSN: 2326-6066 Vol.7 N° 10 2019 págs. 1564 - 1569
    Resumen
    T-cell functional behavior and performance are closely regulated by nutrient availability and the control of metabolism within the T cell. T cells have distinct energetic and anabolic needs when nascently activated, actively proliferating, in naivete, or in a resting, memory state. As a consequence, bioenergetics are key for T cells to mount adequate immune responses in health and disease. Solid tumors are particularly hostile metabolic environments, characterized by low glucose concentration, hypoxia, and low pH. These metabolic conditions in the tumor are known to hinder antitumor immune responses of T cells by limiting nutrient availability and energetic efficiency. In such immunosuppressive environments, artificial modulation of glycolysis, mitochondrial respiratory capabilities, and fatty acid b-oxidation are known to enhance antitumor performance. Reportedly, costimulatory molecules, such as CD28 and CD137, are important regulators of metabolic routes in T cells. In this sense, different costimulatory signals and cytokines induce diverse metabolic changes that critically involve mitochondrial mass and function. For instance, the efficacy of chimeric antigen receptors (CAR) encompassing costimulatory domains, agonist antibodies to costimulatory receptors, and checkpoint inhibitors depends on the associated metabolic events in immune cells. Here, we review the metabolic changes that costimulatory receptors can promote in T cells and the potential consequences for cancer immunotherapy. Our focus is mostly on discoveries regarding the physiology and pharmacology of IL15, CD28, PD-1, and CD137 (4-1BB).
  • Autores: Vasquez, M.; Consuegra-Fernandez, M.; Aranda, F. ; et al.
    Revista: JOURNAL OF IMMUNOLOGY
    ISSN: 0022-1767 Vol.203 N° 3 2019 págs. 696 - 704
    Resumen
    Multiple sclerosis (MS) is a chronic autoimmune disease with no curative treatment. The immune regulatory properties of type I IFNs have led to the approval of IFN-beta for the treatment of relapsing-remitting MS. However, there is still an unmet need to improve the tolerability and efficacy of this therapy. In this work, we evaluated the sustained delivery of IFN-alpha 1, either alone or fused to apolipoprotein A-1 by means of an adeno-associated viral (AAV) system in the mouse model of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. These in vivo experiments demonstrated the prophylactic and therapeutic efficacy of the AAV-IFN-alpha or AAV-IFN-alpha fused to apolipoprotein A-1 vectors in experimental autoimmune encephalomyelitis, even at low doses devoid of hematological or neurologic toxicity. The sustained delivery of such low-dose IFN-alpha resulted in immunomodulatory effects, consisting of proinflammatory monocyte and T regulatory cell expansion. Moreover, encephalitogenic T lymphocytes from IFN-alpha-treated mice re-exposed to the myelin oligodendrocyte glycoprotein peptide in vitro showed a reduced proliferative response and cytokine (IL-17A and IFN-gamma) production, in addition to upregulation of immunosuppressive molecules, such as IL-10, IDO, or PD-1. In conclusion, the results of the present work support the potential of sustained delivery of low-dose IFN-alpha for the treatment of MS and likely other T cell-dependent chronic autoimmune disorders.
  • Autores: Solans, B. P.; López Díaz de Cerio, Ascensión; Elizalde Pérez, Arlette María; et al.
    Revista: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN: 0306-5251 Vol.85 N° 8 2019 págs. 1670 - 1683
    Resumen
    AimsImmunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naive BC patients. MethodsEighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination. Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n=111) were used to validate the model. ResultsTumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P=.04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects. Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis. ConclusionsDendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.
  • Autores: Rodríguez Ruiz, María Esperanza (Autor de correspondencia); Rodriguez, I.; Mayorga Ortiz, Lina Paola; et al.
    Revista: MOLECULAR CANCER THERAPEUTICS
    ISSN: 1535-7163 Vol.18 N° 3 2019 págs. 621 - 631
    Resumen
    Radiotherapy can be synergistically combined with immunotherapy in mouse models, extending its efficacious effects outside of the irradiated field (abscopal effects). We previously reported that a regimen encompassing local radiotherapy in combination with anti-CD137 plus anti-PD-1 mAbs achieves potent abscopal effects against syngeneic transplanted murine tumors up to a certain tumor size. Knowing that TGF beta expression or activation increases in irradiated tissues, we tested whether TGF beta blockade may further enhance abscopal effects in conjunction with the anti-PD-1 plus anti-CD137 mAb combination. Indeed, TGF beta blockade with 1D11, a TGF beta-neutralizing mAb, markedly enhanced abscopal effects and overall treatment efficacy against subcutaneous tumors of either 4T1 breast cancer cells or large MC38 colorectal tumors. Increases in CD8 T cells infiltrating the nonirradiated lesion were documented upon combined treatment, which intensely expressed Granzyme-B as an indicator of cytotoxic effector capability. Interestingly, tumor tissue but not healthy tissue irradiation results in the presence of higher concentrations of TGF beta in the nonirradiated contralateral tumor that showed smad2/3 phosphorylation increases in infiltrating CD8 T cells. In conclusion, radiotherapy-induced TGF beta hampers abscopal efficacy even upon combination with a potent immunotherapy regimen. Therefore, TGF beta blockade in combination with radioimmunotherapy results in greater efficacy.
  • Autores: Aznar Gómez, María Ángela (Autor de correspondencia); Planelles, L.; Perez-Olivares, M.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.7 N° 1 2019 págs. 116
    Resumen
    Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4T1 and B16-F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8(+) T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).
  • Autores: Elgendy, M.; Fusco Morales, Juan Pablo; Segura Ruiz, Victor; et al.
    Revista: INTERNATIONAL JOURNAL OF CANCER
    ISSN: 0020-7136 Vol.145 N° 7 2019 págs. 1991 - 2001
    Resumen
    Sunitinib is one of the most widely used targeted therapeutics for renal cell-cancer (RCC) but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in renal cell-cancer (RCC), we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and following development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in-silico prediction models, 6 predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1 and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function render tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the 6 proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
  • Autores: Schalper, K. A. ; Rodriguez-Ruiz, M. E.; Diez Valle, Ricardo; et al.
    Revista: NATURE MEDICINE
    ISSN: 1078-8956 Vol.25 N° 3 2019 págs. 470 - 476
    Resumen
    Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3¿cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
  • Autores: Elgendy, M.; Fusco Morales, Juan Pablo; Segura Ruiz, Victor; et al.
    Revista: INTERNATIONAL JOURNAL OF CANCER
    ISSN: 0020-7136 Vol.145 N° 7 2019 págs. 1991 - 2001
    Resumen
    Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
  • Autores: Loriot, Y. ; Balar, A. V.; Dreicer, R. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 15 2019
  • Autores: Nagineni, V. V.; Schalper, K.; Desai, S.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.7 2019
  • Autores: Lozano, R.; Castro, E. ; Piulats, J. M.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 7 2019
  • Autores: Etxeberria Uriz, Iñaki; Bolaños Mateo, Elixabet; Teijeira Sánchez, Álvaro; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.79 N° 13 2019
  • Autores: Mielgo, X.; Diaz-Beveridge, R.; Sepulveda, J. M.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 15 2019
  • Autores: Kudo, M.; Matilla, A.; Santoro, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 4 2019
  • Autores: De Andrea, Carlos Eduardo; Abengozar Muela, Marta; García Ros, David; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN: 0023-6837 Vol.99 N° Supl. 1 2019 págs. 1820
  • Autores: Defourny, N.; Medina, A. L.; Tarjuelo, J. L.; et al.
    Revista: RADIOTHERAPY AND ONCOLOGY
    ISSN: 0167-8140 Vol.133 N° Supl. 1 2019 págs. S316 - S317
  • Autores: Marquez-Rodas, I.; Longo, F.; Aix, S. P.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.30 N° Supl. 11 2019
  • Autores: Balar, A. V.; Dreicer, R.; Loriot, Y.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.37 N° 7 2019
  • Autores: Melero Bermejo, Ignacio; Neely, J. ; Sangro Gómez-Acebo, Bruno Carlos; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.30 2019
  • Autores: Rodriguez-Vida, A.; Pérez Gracia, José Luis; Bellmunt, J. (Autor de correspondencia)
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.24 N° 24 2018 págs. 6115 - 6124
    Resumen
    Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer. Overall, these agents have shown objective response rates of around 20% to 23%, which indicates that a significant proportion of patients do not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement in the median duration of response compared with chemotherapy, still only half of the patients develop long-term maintained remissions. Active research is ongoing in several fields, aiming to increase the number of patients that benefit from ICI, and this research is largely based on the development of biomarkers for personalized immunotherapy and novel combinations of ICI with other agents. This article will review ongoing efforts to develop combinations of ICI with other therapeutic strategies in patients with urothelial cancer, including chemotherapy, targeted agents, other immunotherapy strategies, and radiotherapy. (C) 2018 AACR.
  • Autores: Chester, C. (Autor de correspondencia); Fernández de Sanmamed Gutiérrez, Miguel; Wang, J.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.131 N° 1 2018 págs. 49 - 57
    Resumen
    4-1BB (CD137, tumor necrosis factor receptor superfamily 9) is an inducible costimulatory receptor expressed on activated T and natural killer (NK) cells. 4-1BB ligation on T cells triggers a signaling cascade that results in upregulation of antiapoptotic molecules, cytokine secretion, and enhanced effector function. In dysfunctional T cells that have a decreased cytotoxic capacity, 4-1BB ligation demonstrates a potent ability to restore effector functions. On NK cells, 4-1BB signaling can increase antibody-dependent cell-mediated cytotoxicity. Agonistic monoclonal antibodies targeting 4-1BB have been developed to harness 4-1BB signaling for cancer immunotherapy. Preclinical results in a variety of induced and spontaneous tumor models suggest that targeting 4-1BB with agonist antibodies can lead to tumor clearance and durable antitumor immunity. Clinical trials of 2 agonist antibodies, urelumab and utomilumab, are ongoing. Despite initial signs of efficacy, clinical development of urelumab has been hampered by inflammatory liver toxicity at doses > 1 mg/kg. Utomilumab has a superior safety profile, but is a less potent 4-1BB agonist relative to urelumab. Both antibodies have demonstrated promising results in patients with lymphoma and are being tested in combination therapy trials with other immunomodulatory agents. In an effort to optimally leverage 4-1BB-mediated immune activation, the next generation of 4-1BB targeting strategies attempts to decouple the observed antitumor efficacy from the on-target liver toxicity. Multiple therapeutics that attempt to restrict 4-1BB agonism to the tumor microenvironment and minimize systemic exposure have emerged. 4-1BB is a compelling target for cancer immunotherapy and future agents show great promise for achieving potent immune activation while avoiding limiting immune-related adverse events.
  • Autores: Ascierto, P. A. (Autor de correspondencia); Brugarolas, J. ; Buonaguro, L.; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.6 2018 págs. 69
    Resumen
    Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno-oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report.
  • Autores: Iñarrairaegui Bastarrica, Mercedes; Melero Bermejo, Ignacio; Sangro Gómez-Acebo, Bruno Carlos (Autor de correspondencia)
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.24 N° 7 2018 págs. 1518 - 1524
    Resumen
    Treatment of patients with hepatocellular carcinoma (HCC) in the advanced stage remains a great challenge, with very few drugs approved. After decades of failure of immune therapies, immune checkpoint inhibitors have emerged as potentially effective treatments for patients with HCC in the advanced stage. Immune checkpoints, including human cancer, cytotoxic T-lymphocyte protein 4 (CTLA-4), and programmed cell death protein 1 (PD-1), are surface proteins expressed in a variety of immune cells and mostly provide immunosuppressive signals. Monoclonal antibodies able to block these molecules have shown antitumor activity against a wide spectrum of human cancers. Clinical experience with checkpoint inhibitors in HCC includes early trials with the anti-CTLA-4 agent tremelimumab and a large phase II trial with the anti-PD-1 agent nivolumab. The latter has shown strong activity particularly as second-line therapy, both in terms of tumor response and patient survival. At least three topics should be the focus of future research: (i) the search for activity in patients at less-advanced stages, including the adjuvant treatment of patients with resectable or ablatable tumors; (ii) the enhanced efficacy of combination therapies, including particularly the combination with those targeted and locoregional therapies that may have a synergistic effect or act upon mechanisms of primary or acquired resistance to checkpoint inhibitors; and (iii) the identification of clinical features and serumor tissue biomarkers that would allow a better patient selection for individual treatments. Hopefully, ongoing trials will help to design better treatments in the future. (C) 2017 AACR.
  • Autores: Pastor Rodríguez, Fernando; Berraondo López, Pedro; Etxeberria Uriz, Iñaki; et al.
    Revista: NATURE REVIEWS DRUG DISCOVERY
    ISSN: 1474-1776 Vol.17 N° 10 2018 págs. 751 - 767
    Resumen
    Cancer immunotherapy has revolutionized oncology practice. However, current protein and cell therapy tools used in cancer immunotherapy are far from perfect, and there is room for improvement regarding their efficacy and safety. RNA-based structures have diverse functions, ranging from gene expression and gene regulation to pro-inflammatory effects and the ability to specifically bind different molecules. These functions make them versatile tools that may advance cancer vaccines and immunomodulation, surpassing existing approaches. These technologies should not be considered as competitors of current immunotherapies but as partners in synergistic combinations and as a clear opportunity to reach more efficient and personalized results. RNA and RNA derivatives can be exploited therapeutically as a platform to encode protein sequences, provide innate pro-inflammatory signals to the immune system (such as those denoting viral infection), control the expression of other RNAs (including key immunosuppressive factors) post-transcriptionally and conform structural scaffoldings binding proteins that control immune cells by modifying their function. Nascent RNA immunotherapeutics include RNA vaccines encoding cancer neoantigens, mRNAs encoding immunomodulatory factors, viral RNA analogues, interference RNAs and protein-binding RNA aptamers. These approaches are already in early clinical development with promising safety and efficacy results.
  • Autores: Rodríguez Ruiz, María Esperanza; Vanpouille-Box, C.; Melero Bermejo, Ignacio; et al.
    Revista: TRENDS IN IMMUNOLOGY
    ISSN: 1471-4906 Vol.39 N° 8 2018 págs. 644 - 655
    Resumen
    Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia)
    Revista: EUROPEAN UROLOGY
    ISSN: 0302-2838 Vol.74 N° 1 2018 págs. E14
  • Autores: Etxeberria Uriz, Iñaki; Teijeira Sánchez, Álvaro; Montuenga Badía, Luis; et al.
    Revista: CANCER DISCOVERY
    ISSN: 2159-8274 Vol.8 N° 7 2018 págs. 794 - 796
    Resumen
    Cancer genetic alterations and epigenetics control the malignant phenotype of tumor cells and the stroma. Synergistic oncogenic alterations may cooperatively dictate immunogenicity, level of infiltration by immune system cells, and response to immunotherapy in an epistatic fashion. The work of Skoulidis and colleagues shows that concomitant RAS and STK11/LKB1 mutations in non-small cell lung adenocarcinomas result in primary resistance to PD-1-based immunotherapy and poor T-cell infi ltration. (c) 2018 AACR.
  • Autores: De Andrea, Carlos Eduardo; Schalper, K. A. ; Fernández de Sanmamed Gutiérrez, Miguel; et al.
    Revista: CANCER CELL
    ISSN: 1535-6108 Vol.34 N° 6 2018 págs. 876 - 878
    Resumen
    Van den Eynde et al. publish in this issue of Cancer Cell that metastatic colorectal cancer shows marked heterogeneity in T cell infiltration among different lesions and patients. Measurements of T cell infiltration in metastases by immunoscore offer some prognostic information and support immune editing by coevolving adaptive immune responses.
  • Autores: Berraondo López, Pedro (Autor de correspondencia); Aznar Gómez, María Ángela; Perez-Ruiz, E.; et al.
    Revista: CANCER IMMUNOLOGY IMMUNOTHERAPY
    ISSN: 0340-7004 Vol.67 N° 11 2018 págs. 1809 - 1813
  • Autores: Berraondo López, Pedro; Etxeberria Uriz, Iñaki; Ponz Sarvisé, Mariano; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.24 N° 12 2018 págs. 2716 - 2718
    Resumen
    IL12 antitumor activities are mediated by the activation of T and natural killer (NK) lymphocytes to produce IFNg. Systemically, recombinant IL12 has a narrow therapeutic window that favors local delivery, for instance, by gene therapy approaches. IL12 is a powerful partner in immunotherapy combinations with checkpoint inhibitors and adoptive T-cell transfer. (C) 2018 AACR.
  • Autores: Melero Bermejo, Ignacio; Sznol, M.; Tessmer, M. S. (Autor de correspondencia); et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.24 N° 8 2018 págs. 1773 - 1774
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Fernández de Sanmamed Gutiérrez, Miguel; Melero Bermejo, Ignacio
    Revista: TRANSLATIONAL LUNG CANCER RESEARCH
    ISSN: 2218-6751 Vol.7 N° Supl. 4 2018 págs. S356 - S357
  • Autores: Rodríguez Ruiz, María Esperanza; Pérez Gracia, José Luis; Rodríguez, I.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° 5 2018 págs. 1312 - 1319
    Resumen
    Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-alpha and IFN-alpha. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m(2) was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre-and posttreatment PBMC from patients achieving durable stable disease (SD) were studied by IFNc ELISPOT-assays responding to tumor-lysate loaded DC and by TCR beta sequencing. Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-beta and IFN-alpha mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1 beta concentrations, especially in patients presenting SD. IFNc-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
  • Autores: Marabelle, A. (Autor de correspondencia); Andtbacka, R.; Harrington, K.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° 11 2018 págs. 2163 - 2174
    Resumen
    A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Loriot, Y.; Rosenberg, J. E.; et al.
    Revista: EUROPEAN UROLOGY
    ISSN: 0302-2838 Vol.73 N° 3 2018 págs. 462 - 468
    Resumen
    Background: Patients with metastatic urothelial carcinoma (mUC) who progress after platinum-based chemotherapy have had few treatment options and uniformly poor outcomes. Atezolizumab (anti-programmed death-ligand 1) was approved in the USA for cisplatin-ineligible and platinum-treated mUC based on IMvigor210, a phase 2, single-arm, two-cohort study. Objective: To evaluate the efficacy and safety of atezolizumab by the number of prior lines of systemic therapy in patients with pretreated mUC. Design, setting, and participants: IMvigor210 enrolled 315 patients with mUC with progression during or following platinum-based therapy at 70 international sites between May 2014 and November 2014. Key inclusion criteria included age >= 18 yr, creatinine clearance >= 30 ml/min, and Eastern Cooperative Oncology Group performance status 0-1, with no limit on prior lines of treatment. Intervention: Patients in this cohort received atezolizumab 1200 mg intravenously every 3 wk until loss of clinical benefit. Outcome measurements and statistical analysis: Centrally assessed Response Evaluation Criteria In Solid Tumors v1.1 objective response rate (ORR), median duration of response, overall survival (OS), and adverse events were evaluated by prior treatment. Potential differences between subgroups were evaluated using log-rank (for OS) and chi-square (for ORR and adverse events frequencies) testing. Results and limitations: Three hundred and ten patients were efficacy and safety evaluable (median follow-up, 21 mo). Objective responses and prolonged OS occurred across all prespecified subgroups; median duration of response was not reached in most subgroups. In patients without prior systemic mUC therapy (first-line subgroup), ORR was 25% (95% confidence interval: 14-38), and median OS was 9.6 mo (95% confidence interval: 5.9-15.8). No significant differences in efficacy or toxicity by therapy line were observed. Conclusions: Atezolizumab demonstrated comparable efficacy and safety in previously treated patients with mUC across all lines of therapy evaluated. (c) 2017 Published by Elsevier B.V. on behalf of European Association of Urology.
  • Autores: Carles, J. (Autor de correspondencia); Mendez, M. J.; Pinto, A.; et al.
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.14 N° 1 2018 págs. 41 - 50
    Resumen
    Aim: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). Patients & methods: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. Results: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with >= 50% confirmed declines in prostate-specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). Conclusion: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns.
  • Autores: Rodríguez Rodríguez, Javier; Castañón Álvarez, Eduardo; Pérez Gracia, José Luis; et al.
    Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
    ISSN: 2051-1426 Vol.6 2018 págs. 96
    Resumen
    Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1: 1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival -DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32-18.88).
  • Autores: Pérez Gracia, José Luis; Díez-Caballero Alonso, Fernando José; Gurpide Ayarra, Luis Alfonso; et al.
    Revista: ARCHIVOS ESPANOLES DE UROLOGIA
    ISSN: 0004-0614 Vol.71 N° 3 2018 págs. 276 - 280
    Resumen
    OBJECTIVE: Several studies have assessed the role of adding chemotherapy to hormonal treatment for metastatic hormone-sensitive prostate cancer (MHSPC). The objective of this manuscript is to review these studies and to provide recommendations for the management of these patients. METHODS: We identified published clinical trials comparing hormone blockade (HB) with HB plus docetaxel as first-line treatment of HSMPC and we analyzed their results in terms of efficacy and toxicity. RESULTS: Of the 3 trials published, two demonstrated increased overall survival by adding docetaxel to the first-line treatment of MHSPC (CHAARTED and Stampede-Docetaxel studies) and the third one did not show such an advantage (GETUG-AFU15). In the CHAARTED study, the survival advantage was limited to patients presenting high tumor volume. Toxicity was increased in patients who received docetaxel. CONCLUSIONS: The addition of docetaxel to treatment with HB should be considered in patients with MHSPC, especially in those with high tumor volume. However, the toxicity and recent results of trials performed with abiraterone in MHSPC should also be taken in consideration.
  • Autores: Pérez Gracia, José Luis (Autor de correspondencia); Díez-Caballero Alonso, Fernando José; Gurpide Ayarra, Luis Alfonso; et al.
    Revista: ARCHIVOS ESPAÑOLES DE UROLOGIA
    ISSN: 0004-0614 Vol.71 N° 3 2018 págs. 276 - 280
    Resumen
    OBJECTIVE: Several studies have assessed the role of adding chemotherapy to hormonal treatment for metastatic hormone-sensitive prostate cancer (MHSPC). The objective of this manuscript is to review these studies and to provide recommendations for the management of these patients. METHODS: We identified published clinical trials comparing hormone blockade (HB) with HB plus docetaxel as first-line treatment of HSMPC and we analyzed their results in terms of efficacy and toxicity. RESULTS: Of the 3 trials published, two demonstrated increased overall survival by adding docetaxel to the first-line treatment of MHSPC (CHAARTED and Stampede-Docetaxel studies) and the third one did not show such an advantage (GETUG-AFU15). In the CHAARTED study, the survival advantage was limited to patients presenting high tumor volume. Toxicity was increased in patients who received docetaxel. CONCLUSIONS: The addition of docetaxel to treatment with HB should be considered in patients with MHSPC, especially in those with high tumor volume. However, the toxicity and recent results of trials performed with abiraterone in MHSPC should also be taken in consideration.
  • Autores: Compte, M.; Harwood, S. L.; Munoz, I. G.; et al.
    Revista: NATURE COMMUNICATIONS
    ISSN: 2041-1723 Vol.9 N° 1 2018 págs. 4809
    Resumen
    The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with Fc gamma R interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8(N)/(C)EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8(N)/(C)EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8(N)/(C)EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate Fc gamma R interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy.
  • Autores: Teijeira Sánchez, Álvaro; Labiano, S.; Garasa, S.; et al.
    Revista: CANCER IMMUNOLOGY RESEARCH
    ISSN: 2326-6066 Vol.6 N° 7 2018 págs. 798 - 811
    Resumen
    T and NK lymphocytes express CD137 (4-1BB), a costimulatory receptor of the TNFR family whose function is exploitable for cancer immunotherapy. Mitochondria regulate the function and survival of F lymphocytes. herein, we show that CD137 costimulation provided by agonist mAb and CD137L (4-1BBL) induced mitochondria enlargement that resulted in enhanced mitochondrial mass and transmembrane potential in human and mouse CD8(+) T cells. Such mitochondrial changes increased 'T-cell respiratory capacities and were critically dependent on mitochondrial fusion protein OPA-1 expression. Mass and function of mitochondria in rumor-reactive CD8(+) T cells from cancer-hearing mice were invigorated by agonist mAb to CD137, whereas mitochondria) baseline mass and function were depressed in CD137-deficient tumor reactive T cells. Tumor rejection induced by the synergistic combination of adoptive T-cell therapy and agonistic anti-CD 137 WAS critically dependent on OPA-1 expression in transferred CD8(+) T cells. Moreover, stimulation of CD137 with CD137 mAb in shortterm cultures of human tumor-infiltrating lymphocytes led to mitochondria enlargement and increased transmembrane potential. Collectively, these data point to a critical link between mitochondrial morphology and function and enhanced antitumor effector activity upon CD 117 costimulation of T cells. (C)2018 AACR.
  • Autores: Yanguas Andrés, Alba; Garasa, S.; Teijeira Sánchez, Álvaro; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN: 1664-3224 Vol.9 2018 págs. 2084
    Resumen
    The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely important to mount effective distant responses and for the establishment of long term systemic memory. Looking into mechanisms behind lymphocyte egress, we directed our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion in mouse models of melanoma and breast cancer. We also provide evidence of the presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1 interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+ T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic receptor CCR7 augments in tumor in filtrating lymphocytes and in in-vitro de-clustered T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve the transit of activated lymphocytes toward the lymph nodes and their subsequent recirculation.
  • Autores: Ochoa Nieto, Maria del Carmen; Cordeiro Minute, Luna Ridan; López Díaz de Cerio, Ascensión; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.7 N° 2 2018 págs. e1393597
    Resumen
    Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15R alpha, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8(+) T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8(+) T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo. The EGFR(+) human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2(gamma)(-/-)c(-/-) mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1(-/-) mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens.
  • Autores: Gallardo, E.; Mendez-Vidal, M. J.; Pérez Gracia, José Luis; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.20 N° 1 2018 págs. 47 - 56
    Resumen
    The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.
  • Autores: Sanchez-Paulete, A. R. ; Teijeira Sánchez, Álvaro; Quetglas, J. I.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 23 2018 págs. 6643 - 6654
    Resumen
    Multiple lines of evidence indicate a critical role of antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1, respectively, constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to the tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38-and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory mAbs. Therapeutic effects were abolished by CD8 beta T-cell depletion and were enhanced by CD4 T-cell depletion, but not by T regulatory cell predepletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNARdeficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltratingCD8T cells, including those recognizing OVA. Consistently, following the intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T-cell depletion. Significance: These findings demonstrate that transgenic expression of sFLT3L and XCL1 in tumor cells mediates crosspriming of, and elicits potent antitumor activity from, CD8 T lymphocytes, particularly in combination with CD4 T-cell depletion. (C) 2018 AACR.
  • Autores: Azpilicueta Lusarreta, Arantza; Bolaños Mateo, Elixabet; Lang, V. ; et al.
    Revista: ONCOIMMUNOLOGY
    ISSN: 2162-402X Vol.7 N° 1 2018 págs. e1368605
    Resumen
    TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF kappa B activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD137-induced NF kappa B activation in cultured cells and in gene-transferred hepatocytes in vivo, while silencing these deubiquitinases enhanced CD137 costimulation of primary human CD8 T cells. Therefore A20 and CYLD directly downregulate the signaling from a T and NK-cell costimulatory receptor under exploitation for cancer immunotherapy in clinical trials.
  • Autores: Aznar Gómez, María Ángela; Labiano Almiñana, Sara; Diaz-Lagares, A.; et al.
    Revista: CANCER IMMUNOLOGY RESEARCH
    ISSN: 2326-6066 Vol.6 N° 1 2018 págs. 69 - 78
    Resumen
    CD137 (4-1BB) costimulation imprints long-term changes that instruct the ultimate behavior of T cells that have previously experienced CD137 ligation. Epigenetic changes could provide a suitable mechanism for these long-term consequences. Genome-wide DNA methylation arrays were carried out on human peripheral blood CD8(+) T lymphocytes stimulated with agonist monoclonal antibody to CD137, including urelumab, which is in phase I/II clinical trials for cancer immunotherapy. Several genes showed consistent methylation patterns in response to CD137 costimulation, which were confirmed by pyrosequencing in a series of healthy donors. CD96, HHLA2, CCR5, CXCR5, and CCL5 were among the immune-related genes regulated by differential DNA methylation, leading to changes in mRNA and protein expression. These genes are also differentially methylated in naive versus antigen-experienced CD8(+) T cells. The transcription factor TCF1 and the microRNA miR-21 were regulated by DNA methylation upon CD137 costimulation. Such gene-expression regulatory factors can, in turn, broaden the effects of DNA methylation by controlling expression of their target genes. Overall, chromatin remodeling is postulated to leave CD137-costimulated T lymphocytes poised to differentially respond upon subsequent antigen recognition. Accordingly, CD137 connects costimulation during priming to genome-wide DNA methylation and chromatin reprogramming. (C) 2017 AACR.
  • Autores: Perez-Ruiz, E.; Minute, L.; Ochoa Nieto, Maria del Carmen; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018
  • Autores: Herbst, R. S.; Garon, E. B. ; Kim, D. W.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 10 2018 págs. 42
    Resumen
    Background: In the global, open-label, phase 2/3 study KEYNOTE-010, pembro 10¿mg/kg or 2¿mg/kg Q3W improved OS vs docetaxel in pts with previously treated advanced NSCLC with PD-L1 TPS ¿50% and ¿1% (coprimary analyses) at median follow-up of 13.1¿mo. We present long-term results overall, in pts who completed 35 cycles (~2 y) of pembro, and in pts who received a second course of pembro. Methods: Pts aged >18 y with previously treated advanced NSCLC with PD-L1 TPS ¿1% were randomized 1:1:1 to pembro 10¿mg/kg or 2¿mg/kg Q3W, or docetaxel 75¿mg/m2 Q3W. Pts received pembro for 35 cycles, until disease progression/intolerable toxicity. Response was assessed every 9 wk (RECIST 1.1 by independent central review), and survival every 2¿mo posttreatment. There was no difference between pembro doses in the primary analysis, thus doses were pooled in this analysis. Results: As of March 16, 2018, median (range) follow-up was 42.6 (35.2¿53.2) mo overall (N¿=¿1033). Pembro improved OS vs docetaxel in pts with PD-L1 TPS ¿50% (HR, 0.53; 95% CI, 0.42¿0.66; P¿<¿0.00001) and TPS ¿1% (HR, 0.69; 95% CI, 0.60¿0.80; P¿<¿0.00001). In pts with PD-L1 TPS ¿50%, median (95% CI) OS was 16.9 (12.3¿21.4) mo with pembro vs 8.2 (6.4¿9.8) mo with docetaxel; 36-mo OS rates were 35% vs 13%, respectively. Similar to the primary analysis, 16% of pembro pts and 36% of docetaxel pts had grade 3¿5 treatment-related AEs. 79 of 690 pembro pts received 35 treatment cycles (~2 y). 36-mo OS rate among these 79 pts was 99% and 75 (95%) had PR/CR as best response; 72 pts (91%) remained alive. 48 pts (64%) had an ongoing response; median duration of response was not reached (range, 4¿46+ mo). 25 of 79 pts (32%) had PD (investigator review) after stopping 35 cycles of pembro. 14 pts received second course pembro, 5 of whom completed 17 cycles; 6 (43%) had PR, 5 (36%) had SD, and 11 (79%) remained alive. Conclusions: At 43-mo follow-up, pembro continued to prolong OS vs docetaxel in pts with previously treated, PD-L1¿expressing advanced NSCLC, with manageable long-term safety. Most pts who completed 35 cycles (~2 y) of pembro had durable response. The majority of pts with PD by investigator review who received second course pembro had either PR or SD and remained alive.
  • Autores: Rodriguez-Vida, A.; Pérez Gracia, José Luis; Taus, A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018 págs. 326
    Resumen
    Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease associated with poor outcomes. Despite the recent incorporation of several immunotherapy agents targeting the PD-1 pathway, most patients will ultimately experience progressive disease. Moreover, there are no available predictive biomarkers to these novel agents. Clinical studies testing new anticancer drugs embedded with biomarkers analysis are still urgently needed for mUC. Mammalian target of rapamycin (mTOR) is a key intracellular target involved in several cellular signaling pathways, promoting cell proliferation and tumor angiogenesis. TAK-228 is a new investigational mTOR inhibitor of both TORC1 and TORC2. TAK-228 is currently being investigated in several phase II studies as treatment for advanced cancers. Paclitaxel, a taxane chemotherapy that stabilizes microtubules interfering with normal cell division, is a valid treatment option in mUC progressing to platinum-based chemotherapy. The combination of TAK-228 and paclitaxel has shown synergistic activity in bladder cancer cell lines, xenograft models and a phase I trial in advanced solid tumors. Trial design: This is a single-arm open-label phase II study evaluating the efficacy and safety of TAK-228 (given orally on days 2¿¿¿4, 9¿¿¿11, 16¿¿¿18 and 23¿¿¿25 of 28-day cycles) in combination with paclitaxel (given on days 1, 8 and 15). Eligibility criteria include patients with mUC, performance status 0¿¿¿1, prior platinum-based chemotherapy with no limit in number of lines, adequate organ function and measurable disease. The primary endpoint of the study is objective response rate (ORR). Secondary endpoints include safety, tolerability, progression-free survival and overall survival. As an exploratory endpoint, PI3K/AKT/mTOR pathway mutations will be characterized and correlated with clinical outcomes. A maximum of 52 patients will be enrolled in order to obtain 40 evaluable patients. The combination will be considered for further testing should the ORR increase from a historical 10% to¿¿¿26%. A sample size of 40 patients will have a 90% power to detect this change with a 10% alpha risk. The trial is open, and enrollment is ongoing.
  • Autores: Rodríguez Ruiz, María Esperanza; Pérez Gracia, José Luis; Rodríguez, I.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 13 Supl. 2018
  • Autores: Pérez Gracia, José Luis; Pajares Villandiego, María José; Fusco Morales, Juan Pablo; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018 págs. viii651 - viii652
  • Autores: de la Cruz, L.; Sanchez-Margalet, V. ; Berraondo López, Pedro; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.78 N° 4 Supl. 2018
  • Autores: Baraibar Argota, Iosune; Martin-Romano, P.; Fernández de Sanmamed Gutiérrez, Miguel; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018
  • Autores: Necchi, A.; Pérez Gracia, José Luis; Loriot, Y. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018 págs. 328
    Resumen
    Background: After neoadjuvant chemotherapy (NAC), about 20% of pts with muscle-invasive UC are found to have advanced pT-stage or lymph node involvement and 5-year overall survival (OS) of them is¿<¿30%. Tumor samples from these pts may provide information about chemotherapy resistance, and may predict for the activity of new drugs given postoperatively. Alterations of FGFR3 gene represent a therapeutic target in UC and FGFR3 mutations/fusions are enriched in UC Luminal-1 subtype. The pan-FGFR inhibitor INCB054828 has shown promising results in chemotherapy-treated patients with genomic alterations of FGFR3 in tumor tissue and is currently being evaluated in an international phase 2 study (fight-201, NCT02872714). Our study aims to assess the safety and efficacy of adjuvant INCB054828 in pts with FGFR3 mutations/fusions. Trial design: This is an open-label, single-arm, phase 2 study. Subjects will receive INCB054828 at a once-daily (QD) dose of 13.5¿mg on a 2-weeks-on and 1-week-off schedule. Treatment should start within 60 days of surgery and will continue until 12 months, or until the evidence of disease recurrence or unacceptable toxicity onset. Key inclusion criteria are predominant UC histology, FGFR3 mutations/fusions (FoundationOne), bladder or upper tract UC, previous radical cystectomy or nephroureterectomy, previous administration ¿3 cycles of CDDP-based NAC, pT3-4 and/or pN1-3 stage. Relapse-free survival (RFS) is the primary endpoint, assessed every 9 weeks until disease recurrence or death. No interim analyses are planned. It is expected that about 30% of the total screened pts will harbor FGFR3 aberrations. In a single-stage design, with 90% power and one-sided alpha at 0.10, the total enrolled pts will be 56 (H0: 2-y RFS: 30%; H1: 2-y RFS: 45%). Translational research on tissue samples will include associations of immune-inflamed phenotype with next-generation sequencing results and outcome of treatment, and response to any subsequent immunotherapy. The study is sponsored by the EAU-Research Foundation and will involve 15 centers in Europe (EudraCT number 2017-004426-15).
  • Autores: Herbst, R. S.; Garon, E. B.; Kim, D. W.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018 págs. 749 - 749
  • Autores: Ceniceros Paredes, Lucía; Gardeazábal González, Itziar; Rodríguez Remírez, María; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl.3 2018
  • Autores: Baraibar Argota, Iosune; Romano, P. M. ; Fernández de Sanmamed Gutiérrez, Miguel; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 6 2018 págs. 21 - 22
  • Autores: Rodas, I. M. ; Longo, F.; Rodríguez Ruiz, María Esperanza; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.29 N° Supl. 8 2018 págs. 732 - 732
Mostrar más resultados
  • Autores: Pérez Gracia, José Luis; Fernández de Sanmamed Gutiérrez, Miguel; Patiño García, Ana; et al.
    Libro: Proteomic and metabolomic approaches to biomarker discovery
    ISSN: 978-0-12-818607-7 2020 págs. 441 - 466

Proyectos desde 2018

  • Título: Desarrollo de inmunoterapia del cáncer basada en mRNA (ARNMUNE)
    Código de expediente: 0011-1411-2023-000101
    Investigador principal: IGNACIO JAVIER MELERO BERMEJO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
    Fecha de inicio: 05-09-2023
    Fecha fin: 31-12-2025
    Importe concedido: 422.291,90€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo de Medicamentos Innovadores basados en CAR-T: Datos, Inteligencia Artificial, secuenciación MAsiva y Nano-Tecnología (DIAMANTE). Proyecto financiado en el marco de la convocatoria 2023 de proyectos Estratégicos de Gobierno de Navarra
    Código de expediente: 0011-1411-2023-000105
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2023 GN PROYECTOS ESTRATEGICOS DE I+D 2023-2026
    Fecha de inicio: 01-07-2023
    Fecha fin: 31-12-2025
    Importe concedido: 362.076,16€
    Otros fondos: -
  • Título: DeSarrollO de terapias CAR-T innovadoras para el trAtamiento de Tumores Hematológicos y Sólidos (SOCRATHeS)
    Código de expediente: 0011-1411-2022-000053
    Investigador principal: FELIPE LUIS PROSPER CARDOSO, FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025
    Fecha de inicio: 01-05-2022
    Fecha fin: 30-12-2024
    Importe concedido: 371.489,00€
    Otros fondos: -
  • Título: CANCER ORGANOIDS COCULTURED WITH T CELLS AND FIBROBLASTS AS A NEW TOOL TO TEST AND BENCHMARK IMMUNOTHERAPY STRATEGIES
    Código de expediente: 39-2021
    Investigador principal: IGNACIO JAVIER MELERO BERMEJO.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2021 GN Proyectos de Investigación en salud
    Fecha de inicio: 23-12-2021
    Fecha fin: 22-12-2024
    Importe concedido: 79.982,50€
    Otros fondos: -
  • Título: Desarrolo preclinico y translacional de una estrategia inmunoterapia intratumoral consitente en la combinacion de BO-112 y agonistas de STING
    Código de expediente: PDC2021-121769-C22
    Investigador principal: JOSE LUIS PEREZ GRACIA.
    Financiador: AGENCIA ESTATAL DE INVESTIGACION
    Convocatoria: 2021 AEI Proyectos de I+D+i para la realización de pruebas de concepto
    Fecha de inicio: 01-12-2021
    Fecha fin: 30-10-2023
    Importe concedido: 23.000,00€
    Otros fondos: -
  • Título: New targets and designs to improve CAR-T cell based immunotherapy against pancreatic cancer (CarPanTu)
    Código de expediente: PLEC2021-008094
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: AGENCIA ESTATAL DE INVESTIGACION
    Convocatoria: 2021 AEI Proyectos de I+D+i en líneas estratégicas
    Fecha de inicio: 01-11-2021
    Fecha fin: 31-10-2024
    Importe concedido: 100.042,00€
    Otros fondos: Fondos MRR
  • Título: Aplicaciones del estudio multi-ómico de la microbiota al desarrollo de soluciones biotecnológicas innovadoras en el área de la salud (microBiomics)
    Código de expediente: 0011-1411-2021-000106
    Investigador principal: MARIA TERESA HERRAIZ BAYOD, MARIA TERESA HERRAIZ BAYOD.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 31-12-2023
    Importe concedido: 366.577,17€
    Otros fondos: -
  • Título: Administración intratumoral de agentes inmunoterápicos y radioterapia para potenciar los efectos sistémicos y locales antitumorales
    Código de expediente: PI20/00434
    Investigador principal: MARIA ESPERANZA RODRIGUEZ RUIZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 111.320,00€
    Otros fondos: Fondos FEDER
  • Título: Bloqueo de VEGFR· para optimizar la respuesta al tratamiento con radio e inmunotrerapia del cáncer de mama
    Código de expediente: PI20/01737
    Investigador principal: ANA ROUZAUT SUBIRA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2024
    Importe concedido: 99.220,00€
    Otros fondos: Fondos FEDER
  • Título: Nuevos biomarcadores inmunes para la identificación de grupos de riesgo de sufrir infección grave por COVID¿19 mediante citometría de flujo
    Código de expediente: 0011-3638-2020-000004
    Investigador principal: JOSE RAMON YUSTE ARA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2020 GN Proyectos de Investigación en salud
    Fecha de inicio: 21-12-2020
    Fecha fin: 20-12-2021
    Importe concedido: 34.500,00€
    Otros fondos: Fondos FEDER
  • Título: Liderazgo e INnovación en inmunoTERapia del cáncer desde NAvarra
    Código de expediente: 0011-1411-2020-000078
    Investigador principal: IGNACIO JAVIER MELERO BERMEJO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-09-2020
    Fecha fin: 30-11-2022
    Importe concedido: 596.040,00€
    Otros fondos: -
  • Título: Liderazgo e INnovación en inmunoTERapia del cáncer desde NAvarra (LINTERNA)
    Código de expediente: 0011-1411-2020-000075
    Investigador principal: PEDRO BERRAONDO LOPEZ, FERNANDO PASTOR RODRIGUEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022
    Fecha de inicio: 01-09-2020
    Fecha fin: 30-11-2022
    Importe concedido: 590.728,42€
    Otros fondos: -
  • Título: GNI Equipos Irradiador
    Código de expediente: 0011-1508-2020-000009
    Investigador principal: IGNACIO JAVIER MELERO BERMEJO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: FIMA 2020 - GN INDUSTRIA EQUIPOS E INFRAESTRUCTURAS
    Fecha de inicio: 28-07-2020
    Fecha fin: 15-11-2020
    Importe concedido: 172.920,74€
    Otros fondos: -
  • Título: Ensayo clínico fase I/II: nuevo enfoque terapéutico para el tratamiento de tumores sólidos con metástasis hepática.
    Código de expediente: RTC2019-006860-1
    Investigador principal: MARIA ESPERANZA RODRIGUEZ RUIZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2019 AEI RETOS COLABORACIÓN
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2023
    Importe concedido: 594.994,75€
    Otros fondos: -
  • Título: IDENTIFICACIÓN Y DESARROLLO DE TCR TRANSGÉNICOS PARA TERAPIA CELULAR ADOPTIVA DE TUMORES SÓLIDOS
    Código de expediente: 0011-1383-2020-000010 PC197
    Investigador principal: SUSANA INMACULADA INOGES SANCHO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN Proyectos Colaborativos
    Fecha de inicio: 01-12-2019
    Fecha fin: 30-11-2022
    Importe concedido: 137.325,00€
    Otros fondos: -
  • Título: Desarrollo y evaluación de inmunoterapia celular mediante CART alogénicas para el tratamiento de la Leucemia Mieloide Aguda
    Código de expediente: 0011-1383-2020-000010 PC011
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN Proyectos Colaborativos
    Fecha de inicio: 01-12-2019
    Fecha fin: 30-11-2022
    Importe concedido: 180.675,00€
    Otros fondos: -
  • Título: ADMINISTRACION INTRATUMORAL Y DIANIZADA DE AGENTES DE INMUNOTERAPIA PARA EL TRATAMIENTO DEL CANCER
    Código de expediente: PRE2018-085962
    Investigador principal: IRENE OLIVERA VALLE.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2018 - MINECO FPI
    Fecha de inicio: 01-07-2019
    Fecha fin: 30-06-2023
    Importe concedido: 88.250,00€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo EStratégico de terapias CART para el tratamiento de Tumores Hematológicos y Sólidos (DESCARTHeS)
    Código de expediente: 0011-1411-2019-000072
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN PROYECTOS ESTRATEGICOS DE I+D 2019-2021
    Fecha de inicio: 01-04-2019
    Fecha fin: 30-11-2021
    Importe concedido: 164.695,50€
    Otros fondos: -
  • Título: Plataformas automáticas de producción de células CAR T para el tratamiento de leucemia B y linfoma B
    Código de expediente: RTC-2017-6578-1
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO RETOS COLABORACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-10-2021
    Importe concedido: 100.985,84€
    Otros fondos: Fondos FEDER
  • Título: Desarrollo Clínico y Traslacional de Inmunotrapia intratumoral en pacientes con cáncer avanzado.
    Código de expediente: SAF2017-83267-C2-2-R
    Investigador principal: JOSE LUIS PEREZ GRACIA.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO RETOS INVESTIGACION. PROYECTOS DE I+D+i
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2021
    Importe concedido: 84.700,00€
    Otros fondos: Fondos FEDER
  • Título: Humanised-mouse models to implement immunotherapy of cancer
    Código de expediente: CP17/00196
    Investigador principal: MIGUEL FERNANDEZ DE SANMAMED GUTIERREZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES 2017 MIGUEL SERVET TIPO I
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2022