Nuestros investigadores

José Luis Pérez Gracia

Publicaciones científicas más recientes (desde 2010)

Autores: Ajona, Daniel; et al.
Revista: NATURE CANCER
ISSN 2662-1347  Vol. 1  2020  págs. 75 - 85
Harnessing the immune system by blocking the programmed cell death protein 1 (PD-1) pathway has been a major breakthrough in non-small-cell lung cancer treatment. Nonetheless, many patients fail to respond to PD-1 inhibition. Using three syngeneic models, we demonstrate that short-term starvation synergizes with PD-1 blockade to inhibit lung cancer progression and metastasis. This antitumor activity was linked to a reduction in circulating insulin-like growth factor 1 (IGF-1) and a downregulation of IGF-1 receptor (IGF-1R) signaling in tumor cells. A combined inhibition of IGF-1R and PD-1 synergistically reduced tumor growth in mice. This effect required CD8 cells, boosted the intratumoral CD8/Treg ratio and led to the development of tumor-specific immunity. In patients with non-small-cell lung cancer, high plasma levels of IGF-1 or high IGF-1R expression in tumors was associated with resistance to anti-PD-1¿programmed death-ligand 1 immunotherapy. In conclusion, our data strongly support the clinical evaluation of IGF-1 modulators in combination with PD-1 blockade.
Autores: Pérez, José Luis, (Autor de correspondencia); Loriot, Y. ; Rosenberg, J. E.; et al.
Revista: EUROPEAN UROLOGY
ISSN 0302-2838  Vol. 75  Nº 3  2019  págs. E82 - E83
Autores: Berraondo, Pedro, (Autor de correspondencia); Ochoa, María del Carmen; et al.
Revista: BRITISH JOURNAL OF CANCER
ISSN 0007-0920  Vol. 120  Nº 1  2019  págs. 6 - 15
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: Elgendy, M.; Segura, Victoriano; et al.
Revista: INTERNATIONAL JOURNAL OF CANCER
ISSN 0020-7136  Vol. 145  Nº 7  2019  págs. 1991 - 2001
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: Macias, Monica; Rebmann, V.; Mateos, B.; et al.
Revista: CLINICAL CHEMISTRY AND LABORATORY MEDICINE
ISSN 1434-6621  Vol. 57  Nº 10  2019  págs. 1539 - 1545
Background: Exosomes are nanovesicles released by cells that can be detected in blood. Exosomes contain several molecules, such as cytokines that have potential utility as disease biomarkers. The aim of the present work is to compare six different commercial kits suitable for the clinical laboratory in relation to the efficiency and purity of exosome isolation, and their effect in subsequent cytokines analysis. Methods: Serum exosomes were obtained from 10 volunteers using six commercial kits: exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus and Exo-Flow. Exosome concentrations and size distributions were quantified by nanoparticle tracking analysis. Exosome markers CD63, CD9 and TSG101 were determined by Western blot. ApoB and albumin were measured using nephelometry. S100A9, CXCL5 and CXCL12 were measured using a Luminex assay. Results: The concentration of particles obtained between different kits varied by a factor of 100. There was no correlation in particle concentrations extracted between different kits, except between ExoQuick and Exo-Flow. The highest exosome purity was achieved with ExoQuick Plus and exoEasy, while the lowest were achieved with ME and ExoQuick. Albumin was present in all exosome extracts analyzed and ApoB in all except those extracted with Exo-Flow and ME. Cytokine detection varied depending on the purification kit used and there was no correlation in cytokine concentrations between samples obtained with different kits. Conclusions: Both the sample and the type of commercial kit used affect the efficiency and purity of exosome isolation. In addition, the exosome purification method deeply affects the capability to detect and quantify cytokines.
Autores: Rodriguez, I.; et al.
Revista: MOLECULAR CANCER THERAPEUTICS
ISSN 1535-7163  Vol. 18  Nº 3  2019  págs. 621 - 631
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, María Ángela, (Autor de correspondencia); Planelles, L.; Perez-Olivares, M.; et al.
Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN 2051-1426  Vol. 7  Nº 1  2019  págs. 116
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: Hakenberg, O. W., (Autor de correspondencia); Pérez, José Luis; Castellano, D. ; et al.
Revista: EUROPEAN JOURNAL OF CANCER
ISSN 0959-8049  Vol. 107  2019  págs. 186 - 195
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: Datar, I.; Wang, J.; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 25  Nº 15  2019  págs. 4663 - 4673
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: Herbst, R. S., (Autor de correspondencia); Baas, P. ; Pérez, José Luis; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 30  Nº 2  2019  págs. 281 - 289
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: Macias, Monica; Alegre, Estíbaliz; Alkorta-Aranburu, Gorka; et al.
Revista: DISEASE MARKERS
ISSN 0278-0240  Vol. 2019  Nº Article ID 7954921  2019  págs. 1 - 7
Epidermal growth factor receptor (EGFR) mutational testing in advanced non-small-cell lung cancer (NSCLC) is usually performed in tumor tissue, although cfDNA (cell-free DNA) could be an alternative. We evaluated EGFR mutations in cfDNA as a complementary tool in patients, who had already known EGFR mutations in tumor tissue and were treated with either EGFR-tyrosine kinase inhibitors (TKIs) or chemotherapy. We obtained plasma samples from 21 advanced NSCLC patients with known EGFR tumor mutations, before and during therapy with EGFR-TKIs and/or chemotherapy. cfDNA was isolated and EGFR mutations were analyzed with the multiple targeted cobas EGFR Mutation Test v2. EGFR mutations were detected at baseline in cfDNA from 57% of patients. The semiquantitative index (SQI) significantly decreased from the baseline (median = 11, IQR = 9.5-13) to the best response (median = 0, IQR = 0-0, p < 0.01), followed by a significant increase at progression (median = 11, IQR = 11-15, p < 0.01) in patients treated with either EGFR-TKIs or chemotherapy. The SQI obtained with the cobas EGFR Mutation Test v2 did not correlate with the concentration in copies/mL determined by droplet digital PCR. Resistance mutation p.T790M was observed at progression in patients with either type of treatment. In conclusion, cfDNA multiple targeted EGFR mutation analysis is useful for treatment monitoring in tissue of EGFR-positive NSCLC patients independently of the drug received.
Autores: Schalper, K. A. ; Rodriguez-Ruiz, M. E.; Diez Valle, Ricardo; et al.
Revista: NATURE MEDICINE
ISSN 1078-8956  Vol. 25  Nº 3  2019  págs. 470 - 476
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: Pérez, José Luis, (Autor de correspondencia); Castellano, D. ; Climent, M. A.; et al.
Revista: MEDICAL ONCOLOGY
ISSN 1357-0560  Vol. 36  Nº 3  2019  págs. 29
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.; et al.
Revista: NATURE
ISSN 0028-0836  Vol. 569  Nº 7756  2019  págs. 428 - 432
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: Pérez, José Luis; Pita, G.; Segura, V. ; et al.
Revista: JOURNAL OF CLINICAL ONCOLOGY
ISSN 0732-183X  Vol. 37  Nº 15  2019 
Autores: Rodriguez-Vida, A.; Pérez, José Luis; Bellmunt, J., (Autor de correspondencia)
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 24  Nº 24  2018  págs. 6115 - 6124
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: Pérez, José Luis; Díez Caballero, Fernando José; Gurpide, Luis Alfonso; et al.
Revista: ARCHIVOS ESPANOLES DE UROLOGIA
ISSN 0004-0614  Vol. 71  Nº 3  2018  págs. 276 - 280
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: Macias, Monica; Alegre, Estíbaliz; et al.
Revista: ADVANCES IN CLINICAL CHEMISTRY
ISSN 0065-2423  Vol. 83  2018  págs. 73 - 119
Liquid biopsy refers to the molecular analysis in biological fluids of nucleic acids, subcellular structures, especially exosomes, and, in the context of cancer, circulating tumor cells. In the last 10 years, there has been an intensive research in liquid biopsy to achieve a less invasive and more precise personalized medicine. Molecular assessment of these circulating biomarkers can complement or even surrogate tissue biopsy. Because of this research, liquid biopsy has been introduced in clinical practice, especially in oncology, prenatal screening, and transplantation. Here we review the biology, methodological approaches, and clinical applications of the main biomarkers involved in liquid biopsy.
Autores: Berraondo, Pedro, (Autor de correspondencia); Aznar, María Ángela; Perez-Ruiz, E.; et al.
Revista: CANCER IMMUNOLOGY IMMUNOTHERAPY
ISSN 0340-7004  Vol. 67  Nº 11  2018  págs. 1809 - 1813
Autores: Pérez, José Luis, (Autor de correspondencia); Melero, Ignacio Javier;
Revista: TRANSLATIONAL LUNG CANCER RESEARCH
ISSN 2218-6751  Vol. 7  Nº Supl. 4  2018  págs. S356 - S357
Autores: Pérez, José Luis, (Autor de correspondencia); Loriot, Y.; Rosenberg, J. E.; et al.
Revista: EUROPEAN UROLOGY
ISSN 0302-2838  Vol. 73  Nº 3  2018  págs. 462 - 468
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: Pérez, José Luis; Rodríguez, I.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº 5  2018  págs. 1312 - 1319
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: Azpilicueta, Arantza; Lang, V. ; et al.
Revista: ONCOIMMUNOLOGY
ISSN 2162-402X  Vol. 7  Nº 1  2018  págs. e1368605
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: Rodríguez, Javier; Castañón, Eduardo; Pérez, José Luis; et al.
Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER
ISSN 2051-1426  Vol. 6  2018  págs. 96
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, José Luis; Díez Caballero, F.; Gurpide, Luis Alfonso; et al.
Revista: ARCHIVOS ESPAÑOLES DE UROLOGIA
ISSN 0004-0614  Vol. 71  Nº 3  2018  págs. 276 - 280
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: Pita, G.; Pajares, María Josefa; et al.
Revista: CANCER MEDICINE
ISSN 2045-7634  Vol. 7  Nº 7  2018  págs. 3474 - 3483
Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n=3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (p(combined)=5.66x10(-5); ORcombined=2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (p(combined)=1.02x10(-4); ORcombined=2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early-stage NSCLC. PDE10A and ATP10D mRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p=0.01 and p<0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p=0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC.
Autores: Gallardo, E.; Mendez-Vidal, M. J.; Pérez, José Luis; et al.
Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X  Vol. 20  Nº 1  2018  págs. 47 - 56
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: Carles, J., (Autor de correspondencia); Mendez, M. J.; Pinto, A.; et al.
Revista: FUTURE ONCOLOGY
ISSN 1479-6694  Vol. 14  Nº 1  2018  págs. 41 - 50
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: Martinez-Terroba, E.; Behrens, C.; de Miguel, F. J.; et al.
Revista: JOURNAL OF PATHOLOGY
ISSN 0022-3417  Vol. 245  Nº 4  2018  págs. 421 - 432
Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early-stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n=239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p<0.001) and overall survival (p<0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n=114, p=0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p <= 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright (C) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Autores: Herbst, R. S.; Garon, E. B. ; Kim, D. W.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 10  2018  págs. 42
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: Herbst, R. S.; Garon, E. B.; Kim, D. W.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. 749 - 749
Autores:  et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl.3  2018 
Autores: Rodas, I. M. ; Longo, F.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. 732 - 732
Autores: Baraibar, Iosune; Martin-Romano, P.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018 
Autores: Rodriguez-Vida, A.; Pérez, José Luis; Taus, A.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. 326
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: Necchi, A.; Pérez, José Luis; Loriot, Y. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. 328
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: Pérez, José Luis; Pajares, María Josefa; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 29  Nº Supl. 8  2018  págs. viii651 - viii652
Autores: Alfaro, Carlos; et al.
Revista: CANCER TREATMENT REVIEWS
ISSN 0305-7372  Vol. 60  2017  págs. 24 - 31
Interleukin-8 (CXCL8) was originally described asa chemokine whose main function is the attraction of a polymorphonuclear inflammatory leukocyte infiltrate acting on CXCR1/2. Recently, it has been found that tumors very frequently coopt the production of this chemokine, which in this malignant context exerts different pro-tumoral functions. Reportedly, these include angiogenesis, survival signaling for cancer stem cells and attraction of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. Given the fact that in cancer patients IL-8 is mainly produced by tumor cells themselves, its serum concentration has been shown to correlate with tumor burden. Thus, IL-8 serum concentrations have been shown to be useful asa pharmacodynamic biomarker to early detect response to immunotherapy. Finally, because of the roles that IL-8 plays in favoring tumor progression, several therapeutic strategies are being developed to interfere with its functions. Such interventions hold promise, especially for therapeutic combinations in the field of cancer immunotherapy.
Autores: Pérez, José Luis; Sanmamed, M. F.; Bosch, A.; et al.
Revista: CANCER TREATMENT REVIEWS
ISSN 0305-7372  Vol. 53  2017  págs. 79 - 97
The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework the DESIGN guidelines-to-standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. (C) 2017 The Authors. Published by Elsevier Ltd.
Autores: Cueto, F. J.; Garasa, S.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Supl. 12  2017  págs. 44 - 55
Dendritic cells (DCs) are the main professional antigen-presenting cells for induction of T-cell adaptive responses. Cancer cells express tumor antigens, including neoantigens generated by nonsynonymous mutations, but are poor for antigen presentation and for providing costimulatory signals for T-cell priming. Mounting evidence suggests that antigen transfer to DCs and their surrogate presentation on major histocompatibility complex class I and II molecules together with costimulatory signals is paramount for induction of viral and cancer immunity. Of the great diversity of DCs, BATF3/IRF8-dependent conventional DCs type 1 (cDC1) excel at cross-presentation of tumor cell-associated antigens. Location of cDC1s in the tumor correlates with improved infiltration by CD8(+) T cells and tumor-specific T-cell immunity. Indeed, cDC1s are crucial for antitumor efficacy using checkpoint inhibitors and anti-CD137 agonist monoclonal antibodies in mouse models. Enhancement and exploitation of T-cell cross-priming by cDC1s offer opportunities for improved cancer immunotherapy, including in vivo targeting of tumor antigens to internalizing receptors on cDC1s and strategies to increase their numbers, activation and priming capacity within tumors and tumor-draining lymph nodes.
Autores: Elgendy, M. ; Abdel-Aziz, AK. ; Renne, S. L.; et al.
Revista: JOURNAL OF CLINICAL INVESTIGATION
ISSN 0021-9738  Vol. 127  Nº 1  2017  págs. 153 - 168
Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
Autores: Necchi, A., (Autor de correspondencia); Joseph, R. W. ; Loriot, Y.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº 12  2017  págs. 3044 - 3050
Background: Conventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator's discretion: this analysis assessed post-progression outcomes in these patients. Patients and methods: Patients were treated with atezolizumab 1200mg i. v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. Results: In total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for >= 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. Conclusion: In this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma.
Autores: Rodríguez, I.; Barbes, B; et al.
Revista: BRACHYTHERAPY
ISSN 1538-4721  Vol. 16  Nº 6  2017  págs. 1246 - 1251
PURPOSE/OBJECTIVES: Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory monoclonal antibodies (mAb) to act both on irradiated tumor lesions and on tumors at distant, nonirradiated sites. We have recently reported that external beam radiotherapy achieves abscopal effects when combined with antagonist anti-PD1 mAbs and agonist anti-CD137 (4-1BB) mAbs. The goal of this work is to study the abscopal effects of radiotherapy instigated by brachytherapy techniques. METHODS AND MATERIALS: Mice bearing a subcutaneous colorectal carcinoma, MC38 (colorectal cancer), in both flanks were randomly assigned to receive brachytherapy or not (8 Gy × three fractions) to only one of the two grafted tumors, in combination with intraperitoneal immunostimulatory monoclonal antibodies (anti-PD1, anti-CD137, and/or their respective isotype controls). To study the abscopal effects of brachytherapy, we established an experimental set up that permits irradiation of mouse tumors sparing a distant site resembling metastasis. Such second nonirradiated tumor was used as indicator of abscopal effect. Tumor size was monitored every 2 days. RESULTS: Abscopal effects on distant nonirradiated subcutaneous tumor lesions of transplanted MC38-derived tumors only took place when brachytherapy was combined with immunostimulatory anti-PD1 and/or anti-CD137 mAbs. CONCLUSIONS: Our results demonstrate that immunotherapy-potentiated abscopal effects can be attained by brachytherapy. Accordingly, immunotherapy plus brachytherapy combinations are suitable for clinical translation.
Autores: Bellmunt, J.; Kerst, J. M.; Vazquez, F.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº 7  2017  págs. 1517 - 1522
Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine. Patients and methods: This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III. Results: Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-to 4-related adverse events were seen in 41% patients with no difference between the two arms. Conclusion: This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously.
Autores: Sanmamed, M. F. ; Pérez, José Luis; Schalper, K. A. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº 8  2017  págs. 1988 - 1995
Background: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. Patients and methods: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. Results: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P < 0.001), and significantly increased upon progression (P = 0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P < 0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P < 0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. Conclusions: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.
Autores: Balar, A. V.; Galsky, M. D.; Rosenberg, J. E.; et al.
Revista: LANCET
ISSN 0140-6736  Vol. 389  Nº 10064  2017  págs. 67 - 76
Background First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients. Methods For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecified subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652. Findings Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17.2 months' median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2.7 months (2.1 to 4.2). Median overall survival was 15.9 months (10.4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer. Funding F Hoff mann-La Roche, Genentech.
Autores: Garcia Donas, J. ; Font, A. ; Perez Valderrama, B. ; et al.
Revista: LANCET ONCOLOGY
ISSN 1470-2045  Vol. 18  Nº 5  2017  págs. 672 - 681
Background Maintenance therapy improves outcomes in various tumour types, but cumulative toxic effects limit the choice of drugs. We investigated whether maintenance therapy with vinflunine would delay disease progression in patients with advanced urothelial carcinoma who had achieved disease control with first-line chemotherapy. Methods We did a randomised, controlled, open-label, phase 2 trial in 21 Spanish hospitals. Eligible patients had locally advanced, surgically unresectable, or metastatic transitional-cell carcinoma of the urothelial tract, adequate organ function, and disease control after four to six cycles of cisplatin and gemcitabine (carboplatin allowed after cycle four). Patients were randomly assigned (1: 1) to receive vinflunine or best supportive care until disease progression. We initially used block randomisation with a block size of six. Four lists were created for the two stratification factors of starting dose of vinflunine and presence of liver metastases. After a protocol amendment, number of cisplatin and gemcitabine cycles was added as a stratification factor, and eight lists were created, still with a block size of six. Finally, we changed to a minimisation procedure to reduce the risk of imbalance between groups. Vinflunine was given every 21 days as a 20 min intravenous infusion at 320 mg/m(2) or at 280 mg/m(2) in patients with an Eastern Cooperative Oncology Group performance status score of 1, age 75 years or older, previous pelvic radiotherapy, or creatinine clearance lower than 60 mL/min. The primary endpoint was median progression-free survival longer than 5.3 months in the vinflunine group, assessed by modified intention to treat. Comparison of progression-free survival between treatment groups was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01529411. Findings Between April 12, 2012, and Jan 29, 2015, we enrolled 88 patients, of whom 45 were assigned to receive vinflunine and 43 to receive best supportive care. One patient from the vinflunine group was lost to follow-up immediately after randomisation and was excluded from the analyses. One patient in the best supportive care group became ineligible for the study and did not receive treatment due to a delay in enrolment, but was included in the intention-to-treat efficacy analysis. After a median follow-up of 15.6 months (IQR 8.5-26.0), 29 (66%) of 44 patients in the vinflunine group had disease progression and 24 (55%) had died, compared with 36 (84%) of 43 patients with disease progression and 32 (74%) deaths in the best supportive care group. Median progression-free survival was 6.5 months (95% CI 2.0-11.1) in the vinflunine group and 4.2 months (2.1-6.3) in the best supportive care group (hazard ratio 0.59, 95% CI 0.37-0.96, p= 0.031). The most common grade 3 or 4 adverse events were neutropenia (eight [18%] of 44 in the vinflunine group vs none of 42 in the best supportive care group), asthenia or fatigue (seven [16%] vs one [2%]), and constipation (six [14%] vs none). 18 serious adverse events were reported in the vinflunine group and 14 in the best supportive care group. One patient in the vinflunine group died from pneumonia that was deemed to be treatment related. Interpretation In patients with disease control after first-line chemotherapy, progression-free survival exceeded the acceptable threshold with vinflunine maintenance therapy. Moreover, progression-free survival was longer with vinflunine maintenance therapy than with best supportive care. Vinflunine maintenance had an acceptable safety profile. Further studies of the role of vinflunine are warranted.
Autores: Stenzl, A.; Feyerabend, S. ; Syndikus, I.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Supl 5  2017  págs. 1149P
Autores: Marquez Rodas, I.; López-Tarruella Cobo, S.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Suppl. 5  2017  págs.  LBA20
Autores: Pérez, José Luis; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  Nº Supl. 11  2017  págs. 48P
Autores: Datar, I. ; Sanmamed, M. F.; Choi, J. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  2017  págs. 5 - 5
Autores: Necchi, A.; Joseph, R. W.; Loriot, Y. ; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 28  2017  págs.  852PD
Autores: Molina, J.; Herbst, R.; Baas, P.; et al.
Revista: ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY
ISSN 1743-7555  Vol. 13  Nº Supl.2   2017  págs. 68 - 69
Autores: Melero, Ignacio Javier, (Autor de correspondencia); Berraondo, Pedro; et al.
Revista: CANCER DISCOVERY
ISSN 2159-8290  Vol. 6  Nº 12  2016  págs. 1312 - 1314
Surgery remains our strongest treatment pillar against early stages of cancer. In a number of instances, the curative potential of surgery can be enhanced by treatments given before (neoadjuvant) or after (adjuvant) surgical procedures. Immunomodulation has emerged as a powerful tool to fight metastatic disease across cancer histologies and goes now to be tested at earlier surgically amenable stages. The work by Liu and colleagues in this issue provides solid preclinical evidence in support of neoadjuvant immunotherapy over adjuvant approaches.
Autores: Azpilikueta, A.; Agorreta, J; Pérez, José Luis; et al.
Revista: JOURNAL OF THORACIC ONCOLOGY
ISSN 1556-0864  Vol. 11  Nº 4  2016  págs. 524 - 536
INTRODUCTION: Anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (PD-L1) antagonist monoclonal antibodies (mAbs) against metastatic non-small cell lung cancer with special efficacy in patients with squamous cell lung cancer are being developed in the clinic. However, robust and reliable experimental models to test immunotherapeutic combinations in squamous lung tumors are still lacking. METHODS: We generated a transplantable squamous cell carcinoma cell line (UN-SCC680AJ) from a lung tumor induced by chronic N-nitroso-tris-chloroethylurea mutagenesis in A/J mice. Tumor cells expressed cytokeratins, overexpressed p40, and lacked thyroid transcription factor 1, confirming the squamous lineage reported by histological analysis. More than 200 mutations found in its exome suggested potential for antigenicity. Immunocompetent mice subcutaneously implanted with this syngeneic cell line were treated with anti-CD137 and/or anti-PD-1 mAbs and monitored for tumor growth/progression or assessed for intratumoral leukocyte infiltration using immunohistochemical analysis and flow cytometry. RESULTS: In syngeneic mice, large 12-day-established tumors derived from the transplantable cell line variant UN-SCC680AJ were amenable to curative treatment with anti-PD-1, anti-PD-L1, or anti-CD137 immunostimulatory mAbs. Single-agent therapies lost curative efficacy when treatment was started beyond day +17, whereas a combination of anti-PD-1 plus anti-CD137 achieved complete rejections. Tumor cells expressed weak baseline PD-L1 on the plasma membrane, but this could be readily induced by interferon-¿. Combined treatment efficacy required CD8 T cells and induced a leukocyte infiltrate in which T lymphocytes co-expressing CD137 and PD-1 were prominent. CONCLUSIONS: These promising results advocate the use of combined anti-PD-1/PD-L1 plus anti-CD137 mAb immunotherapy for the treatment of squamous non-small cell lung cancer in the clinical setting.
Autores: Alfaro, Carlos; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 22  Nº 15  2016  págs. 3924 - 3936
PURPOSE: Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes. EXPERIMENTAL DESIGN: MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures. RESULTS: IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset. CONCLUSIONS: IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control.
Autores: Alegre, Estíbaliz; Restituto, Patricia; et al.
Revista: TUMOR BIOLOGY
ISSN 1010-4283  Vol. 37  Nº 10  2016  págs. 13687 - 13694
Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %. Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median. Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations.
Autores: Alegre, Estíbaliz; Pérez, José Luis; et al.
Revista: CLINICA CHIMICA ACTA
ISSN 0009-8981  Vol. 454  2016  págs. 28 - 32
Background: Malignant melanoma is an aggressive cancer with an increasing incidence. Exosomes are actively secreted microvesicles, whose characteristics reflect those of the cell they are originated in. The aim of this study was to identify and evaluate the presence of the melanoma biomarlcers MIA, S100B and tyrosinase-related protein 2 (TYRP2) in exosomes and their potential clinical utility. Methods: Serum samples were obtained from stage IV melanoma patients, melanoma-free patients and healthy controls. Exosomes were precipitated and TYRP2, MIA and S100B concentrations were quantified in serum, exosomes, and exosome-free serum. Results: Both MIA and S100B were detected in exosomes and correlated significantly with serum concentrations (S100B: r = 0.968; MIA: r = 0.799; p < 0.001). MIA and S100B concentrations in exosomes were significantly higher in melanoma patients than in healthy controls and disease-free patients. However, TYRP2 concentrations in exosomes did not differ between these three groups. ROC curves analysis rendered AUCs for MIA of 0.883 (p < 0.01) and of 0.840 for S100B (p < 0.01). Patients with exosome MIA concentration higher than 2.5 mu g/L showed shorter median survival related to those with lower level (4 versus 11 months; p < 0.05). Conclusions: MIA and S100B can be detected in exosomes from melanoma patients and their quantification presents diagnostic and prognostic utility.
Autores: Rodriguez, I.; Garasa, S.; et al.
Revista: CANCER RESEARCH
ISSN 0008-5472  Vol. 76  Nº 20  2016  págs. 5994 - 6005
Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8+ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFN¿ in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8+ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation.
Autores: Cambeiro, Felix Mauricio; Moreno, Marta; et al.
Revista: BRACHYTHERAPY
ISSN 1873-1449  Vol. 15  Nº 2  2016  págs. 127 - 135
Purpose: To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012. Methods and Materials: Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001-2007, n = 183) and HDR2 (2007-2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (¿/ß = 1.2) prostate D90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively (p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group (p = 0.001). Results: After a median followup of 7.4 years (range, 2-11.2), there was no difference in adverse grade ¿ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ¿3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ¿2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ¿3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively (p = ns). Conclusions: HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years.
Autores: Roman, M.; Lopez, I.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs. 1270P
Autores: Herbst, R. S.; Martin-Liberal, J.; Calvo, E.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl.6  2016  págs.  LBA38
Autores: Herbst, R. S.; Baas, P.; Kim, D. W.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl.6  2016  págs. LBA48
Autores: Pérez, José Luis; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs. 1055O
Autores: Loriot, Y.; Rosenberg, J. E.; Powles, T. B.; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 27  Nº Supl. 6  2016  págs.  783P
Autores: Azpilicueta, Arantza; Sánchez-Paulete, A. R.; et al.
Revista: ONCOIMMUNOLOGY
ISSN 2162-4011  Vol. 5  Nº 1  2015  págs. e1062967
Hypoxia is a common feature in solid tumors that has been implicated in immune evasion. Previous studies from our group have shown that hypoxia upregulates the co-stimulatory receptor CD137 on activated T lymphocytes and on vascular endothelial cells. In this study, we show that exposure of mouse and human tumor cell lines to hypoxic conditions (1% O2) promotes CD137 transcription. However, the resulting mRNA is predominantly an alternatively spliced form that encodes for a soluble variant, lacking the transmembrane domain. Accordingly, soluble CD137 (sCD137) is detectable by ELISA in the supernatant of hypoxia-exposed cell lines and in the serum of tumor-bearing mice. sCD137, as secreted by tumor cells, is able to bind to CD137-Ligand (CD137L). Our studies on primed T lymphocytes in co-culture with stable transfectants for CD137L demonstrate that tumor-secreted sCD137 prevents co-stimulation of T lymphocytes. Such an effect results from preventing the interaction of CD137L with the transmembrane forms of CD137 expressed on T lymphocytes undergoing activation. Indeed, silencing CD137 with shRNA renders more immunogenic tumor-cell variants upon inoculation to immunocompetent mice but which readily grafted on immunodeficient or CD8+ T-cell-depleted mice. These mechanisms are interpreted as a molecular strategy deployed by tumors to repress lymphocyte co-stimulation via CD137/CD137L.
Autores: Alfaro, Carlos; Echeveste, José Ignacio; et al.
Revista: ONCOIMMUNOLOGY
ISSN 2162-4011  Vol. 4  Nº 12  2015  págs. e1054597
CD137 (4-1BB) is a surface marker discovered on activated T lymphocytes. However, its expression pattern is broader and has also been described on activated NK cells, B-cells and myeloid cells including mature dendritic cells. In this study, we have immunostained for CD137 on paraffin-embedded lymphoid tissues including tonsils, lymph nodes, ectopic tertiary lymphoid tissue in Hashimoto thyroiditis and cancer. Surprisingly, immunostaining mainly decorates intrafollicular lymphocytes in the tissues analyzed, with only scattered staining in interfollicular areas. Moreover, pathologic lymphoid follicles in follicular lymphoma and tertiary lymphoid tissue associated to non-small cell lung cancer showed a similar pattern of immunostaining. Multicolor flow cytometry demonstrated that CD137 expression was restricted to CD4+ CXCR5+ follicular T helper lymphocytes in tonsils and lymph nodes. Short term culture of lymph node cell suspensions in the presence of an agonist anti-CD137 mAb or CD137-ligand results in the functional upregulation of TFH cells, including CD40L surface expression and cytokine production, in three out of six cases. As a consequence, immunostimulatory monoclonal antibodies, anti-CD137 mAb such as urelumab and PF-05082566 should be expected to primarily act on this lymphocyte subset, thus modifying ongoing humoral immune responses.
Autores: Lozano, María D; Subtil, José Carlos; et al.
Revista: INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY
ISSN 1066-8969  Vol. 23  Nº 2  2015  págs. 111 - 115
As a result of therapeutic advances, a revolution is taking place in the lung cancer field with major implications for pathologic diagnosis and tissue management. We report a case of a non-small cell lung carcinoma patient with coexistence of EGFR mutations and ALK-EML4 rearrangements that responded to EGFR inhibitors and in which the development of a new resistance mutation in exon 20 of EGFR-determined treatment resistance. All the molecular determinations were performed in cytological samples. To our knowledge, this is the first case reported with these characteristics, and the 11th case described with coexistence of EGFR mutations and ALK-EML4 rearrangements. The EGFR L858R mutation in exon 21 was found at diagnosis, and the patient presented a 4-year response to erlotinib. On progression, the T790M resistance mutation in the EGFR exon 20 was also confirmed in cytological samples. At this point, fluorescence in situ hybridization also detected ALK-EML4 translocation. This case emphasizes the usefulness of cytological samples for molecular analysis in lung adenocarcinoma, as well as the relevance of repeating biopsies/fine-needle aspirations in tumor recurrences to assess the mutation profile of the disease.
Autores: Fernández, Sara; Rodriguez, C.; et al.
Revista: CLINICAL CHEMISTRY
ISSN 0009-9147  Vol. 61  Nº 1  2015  págs. 297 - 304
BACKGROUND: Around 50% of cutaneous melanomas harbor the BRAF(V600E) mutation and can be treated with BRAF inhibitors. DNA carrying this mutation can be released into circulation as cell-free BRAF(V600E) (cfBRAF(V600E)). Droplet digital PCR (ddPCR) is an analytically sensitive technique for quantifying small concentrations of DNA. We studied the plasma concentrations of cfBRAF(V600E) by ddPCR in patients with melanoma during therapy with BRAF inhibitors. METHODS: Plasma concentrations of cfBRAF(V600E) were measured in 8 controls and 20 patients with advanced melanoma having the BRAF(V600E) mutation during treatment with BRAF inhibitors at baseline, first month, best response, and progression. RESULTS: The BRAF(V600E) mutation was detected by ddPCR even at a fractional abundance of 0.005% in the wild-type gene. Agreement between tumor tissue BRAF(V600E) and plasma cfBRAF(V600E) was 84.3%. Baseline cfBRAF(V600E) correlated with tumor burden (r = 0.742, P < 0.001). cfBRAF(V600E) concentrations decreased significantly at the first month of therapy (basal median, 216 copies/mL; Q1-Q3, 27-647 copies/mL; first response median, 0 copies/mL; Q1-Q3, 0-49 copies/mL; P < 0.01) and at the moment of best response (median, 0 copies/mL; Q1-Q3, 0-33 copies/mL; P < 0.01). At progression, there was a significant increase in the concentration of cfBRAF(V600E) compared with best response (median, 115 copies/mL; Q1-Q3, 3-707 copies/mL; P = 0.013). Lower concentrations of basal cfBRAF(V600E) were significantly associated with longer overall survival and progression-free survival (27.7 months and 9 months, respectively) than higher basal concentrations (8.6 months and 3 months, P < 0.001 and P = 0.024, respectively). CONCLUSIONS: cfBRAF(V600E) quantification in plasma by ddPCR is useful as a follow-up to treatment response in patients with advanced melanoma.
Autores: Sadaba, María Belén; Campanero, MA; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 2  2014  págs. e89747
Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron. PATIENTS AND METHODS: Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA). RESULTS: From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p¿=¿0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration. CONCLUSIONS: Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy.
Autores: Fernández, Sara; et al.
Revista: CLINICA CHIMICA ACTA
ISSN 0009-8981  Vol. 429  2014  págs. 168 - 174
BRAF V600 mutation has been reported in more than 50% of melanoma cases and its presence predicts clinical activity of BRAF inhibitors (iBRAF). We evaluated the rote of MIA, S100 and LDH to monitor iBRAF efficiency in advanced melanoma patients presenting BRAF V600 mutations. This was a prospective study of melanoma patients harboring the BRAF V600 mutation and treated with iBRAF within a clinical trial (dabrafenib) or as part of an expanded access program (vemurafenib). MIA, S100 and LDH were analyzed in serum at baseline, and every 4-6 weeks during treatment. Eighteen patients with melanoma stages IIIc-IV were enrolled with 88.8% of response rate to iBRAF. Baseline concentrations of all the tumor markers correlated with tumor burden. MIA and S100 concentrations decreased significantly one month after the beginning of treatment and, upon progression, their concentrations increased significantly above the minimum levels previously achieved. MIA levels lower than 9 mu g/L one month after the beginning of treatment and S100 concentrations lower than 0.1 mu g/L at the moment of best response were associated With improved progression-free survival. In conclusion, MIA and S100 are useful to monitor response in melanoma patients treated with iBRAF.
Autores: Prior, Celia; Pérez, José Luis; Garcia-Donas J; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 1  2014 
Purpose: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. Methods: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. Results: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. Conclusions: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
Autores: Caicedo C; Garcia-Velloso, Maria Jose; Lozano, María D; et al.
Revista: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN 1619-7070  Vol. 41  Nº 11  2014  págs. 2058-65
PURPOSE: The tumour molecular profile predicts the activity of epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). However, tissue availability and tumour heterogeneity limit its assessment. We evaluated whether [(18)F]FDG PET might help predict KRAS and EFGR mutation status in NSCLC. METHODS: Between January 2005 and October 2011, 340 NSCLC patients were tested for KRAS and EGFR mutation status. We identified patients with stage III and IV disease who had undergone [(18)F]FDG PET/CT scanning for initial staging. SUVpeak, SUVmax and SUVmean of the single hottest tumour lesions were calculated, and their association with KRAS and EGFR mutation status was assessed. A receiver operator characteristic (ROC) curve analysis and a multivariate analysis (including SUVmean, gender, age and AJCC stage) were performed to identify the potential value of [(18)F]FDG PET/CT for predicting KRAS mutation. RESULTS: From 102 patients staged using [(18)F]FDG PET/CT, 28 (27%) had KRAS mutation (KRAS+), 22 (22%) had EGFR mutation (EGFR+) and 52 (51%) had wild-type KRAS and EGFR profiles (WT). KRAS+ patients showed significantly higher [(18)F]FDG uptake than EGFR+ and WT patients (SUVmean 9.5, 5.7 and 6.6, respectively; p¿<¿0.001). No significant differences were observed in [(18)F]FDG uptake between EGFR+ patients and WT patients. ROC curve analysis for KRAS mutation status discrimination yielded an area under the curve of 0.740 for SUVmean (p¿<¿0.001).
Autores: Pérez, José Luis; et al.
Revista: CURRENT OPINION IN IMMUNOLOGY
ISSN 0952-7915  Vol. 27  2014  págs. 89 - 97
Inhibitory receptors on immune system cells respond to membrane-bound and soluble ligands to abort or mitigate the intensity of immune responses by raising thresholds of activation, halting proliferation, favoring apoptosis or inhibiting/deviating effector function differentiation. Such evolutionarily selected inhibitory mechanisms are termed check-points and therefore check-point inhibitors empower any ongoing anti-cancer immune response that might have been too weak or exhausted. Monoclonal antibodies (mAb) interfering with CTLA-4-CD80/86, PD-1 - PD-L1, TIM-3-GAL9 and LAG3-MHC-II belong to this category of check-point inhibitors. The anti-CTLA-4 mAb ipilimumab has been approved for metastatic melanoma. Anti-PD-1 and anti-PD-L1 mAbs have shown extremely encouraging clinical activity. The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients.
Autores: Alfaro, Carlos; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 20  Nº 22  2014  págs. 5697-5707
IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.
Autores: Alfaro, Carlos; Rodriguez, A.; et al.
Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN 1137-6627  Vol. 36  Nº 3  2013  págs. 519 - 537
Dendritic cells (DC) are cells of hematopoietic origin, which constitutively express MHC class I and II, and are functionally the most potent inducers of T-lymphocyte activation and proliferation. CD8+ T lymphocytes proliferate and acquire cytotoxic functions upon recognition of their cognate antigen on the surface of one or various dendritic cells with which they interact. However, only some DC subsets are able to present antigen to cytotoxic T cell precursors as taken up from extracellular sources. This function is termed cross-presentation (in Spanish, presentacion cruzada or presentacion subrogada) and requires shuttle mechanisms from phagosomes to the cytosol for antigen processing. It has been demonstrated that the differentiation of DC with these capabilities is dependent on FLT-3L and the transcription factor BATF3. They express peculiar functions and differentiation markers. These cells are distinguished in mice by surface CD8 alpha features, while CD141 (BDCA-3) marks these cells in the human. These subpopulations are capable of selective internalization of necrotic cell debris by means of their CLEC9A lectin which is a receptor for extracellular polymerized actin. Expression of the chemokine receptor XCR1 favours contact with CD8+ T cells. Therapeutic vaccination with tumour antigens using DC is a strategy under development for the treatment of cancer. The use of DC subsets with more prominent capabilities for cross-presentation would mimic the natural mechanisms of immunization to induce cytolitic T lymphocytes. In vivo targeting of antigens with monoclonal antibodies against DEC-205 or CLEC9A attains very robust immune responses and is a strategy undergoing clinical trials for chronic viral diseases and malignancies.
Autores: Ajona, Daniel; Pajares, María Josefa; et al.
Revista: JOURNAL OF THE NATIONAL CANCER INSTITUTE
ISSN 1460-2105  Vol. 105  Nº 18  2013  págs. 1385 - 1393
BACKGROUND: There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments. METHODS: We assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test. RESULTS: Lung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93). CONCLUSIONS: Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.
Autores: Sangro, Bruno; Gomez-Martin C; de la Mata M; et al.
Revista: JOURNAL OF HEPATOLOGY
ISSN 0168-8278  Vol. 59  Nº 1  2013  págs. 81-88
Background & Aims: Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients. Methods: Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B). Results: A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response. Conclusions: Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Autores: Melero, Ignacio Javier; Grimaldi, A.M.; Pérez, José Luis; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 19  Nº 5  2013  págs. 997-1008
Immune system responses are under the control of extracellular biomolecules, which express functions in receptors present on the surface of cells of the immune system, and thus are amenable to be functionally modulated by monoclonal antibodies. Some of these mechanisms are activating and dictate whether the response ensues, while others play the role of powerful repressors. Antagonist antibodies acting on such repressors result in enhanced immune responses, a goal that is also achieved with agonist antibodies acting on the activating receptors. With these simple logics, a series of therapeutic agents are under clinical development and one of them directed at the CTL-associated antigen 4 (CTLA-4) inhibitory receptor (ipilimumab) has been approved for the treatment of metastatic melanoma. The list of antagonist agents acting on repressors under development includes anti-CTLA-4, anti-PD-1, anti-PD-L1 (B7-H1), anti-KIR, and anti-TGF-ß. Agonist antibodies currently being investigated in clinical trials target CD40, CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNF receptor (GITR). A blossoming preclinical pipeline suggests that other active targets will also be tested in patients in the near future. All of these antibodies are being developed as conventional monoclonal immunoglobulins, but other engineered antibody formats or RNA aptamers are under preclinical scrutiny. The "dark side" of these immune interventions is that they elicit autoimmune/inflammatory reactions that can be severe in some patients. A critical and, largely, pending subject is to identify reliable predictive biomarkers both for efficacy and immune toxicity. Preclinical and early clinical studies indicate a tremendous potential to further improve efficacy, using combinations from among these new agents that frequently act in a synergistic fashion. Combinations with other more conventional means of treatment such as radiotherapy, chemotherapy, or cancer vaccines also hold much promise.
Autores: Guillén-Grima, F; et al.
Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X  Vol. 14  Nº 11  2012  págs. 835-41
The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. METHODS: From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. RESULTS: Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in
Autores: Belza, Idoia; et al.
Revista: ONCOIMMUNOLOGY
ISSN 2162-4011  Vol. 1  Nº 9  2012  págs. 1527-36
Cardiotrophin-1 (CT-1/CTF1) is a member of the interleukin-6 (IL-6) family of cytokines that stimulates STAT-3 phosphorylation in cells bearing the cognate receptor. We report that Ctf1(-/-) mice (hereby referred to as CT-1(-/-) mice) are resistant to the hepatic engraftment of MC38 colon carcinoma cells, while these cells engraft normally in the mouse subcutaneous tissue. Tumor intake in the liver could be enhanced by the systemic delivery of a recombinant adenovirus encoding CT-1, which also partly rescued the resistance of CT-1(-/-) mice to the hepatic engraftment of MC38 cells. Moreover, systemic treatment of wild-type (WT) mice with a novel antibody-neutralizing mouse CT-1 also reduced engraftment of this model. Conversely, experiments with Panc02 pancreatic cancer and B16-OVA melanoma cells in CT-1(-/-) mice revealed rates of hepatic engraftment similar to those observed in WT mice. The mechanism whereby CT-1 renders the liver permissive for MC38 metastasis involves T lymphocytes and natural killer (NK) cells, as shown by selective depletion experiments and in genetically deficient mice. However, no obvious changes in the number or cell killing capacity of liver lymphocytes in CT-1(-/-) animals could be substantiated. These findings demonstrate that the seed and soil concept to understand metastasis can be locally influenced by cytokines as well as by the cellular immune system
Autores: Alfaro, Carlos; et al.
Revista: Cancer Discovery
ISSN 2159-8274  Vol. 2  Nº 7  2012  págs. 608 - 623
Autores: Sandra Hervas-Stubbs; Pérez, José Luis; Rouzaut, Ana; et al.
Revista: CLINICAL CANCER RESEARCH
ISSN 1078-0432  Vol. 17  Nº 9  2011  págs. 2619 - 2627
Autores: Alfaro, Carlos; et al.
Revista: PLoS One
ISSN 1932-6203  Vol. 6  Nº 3  2011  págs. e17922
IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation.
Autores: Lozano, María D; Zulueta, Javier J; Echeveste, José Ignacio; et al.
Revista: ONCOLOGIST
ISSN 1083-7159  Vol. 16  Nº 6  2011  págs. 877 - 885
The mutation status was identical in patients who had both biopsies and cytological samples analyzed. Conclusion. Assessment of EGFR and K-ras mutations in cytological samples is feasible and comparable with biopsy results, making individualized treatment
Autores: Bellmunt, J; González-Larriba, JL; Prior, Celia; et al.
Revista: ANNALS OF ONCOLOGY
ISSN 0923-7534  Vol. 22  Nº 12  2011  págs. 2646-2653
Autores: Alfaro, Carlos; et al.
Revista: PLoS One
ISSN 1932-6203  Vol. 6  Nº 12  2011  págs. e229300
Moreover, when mouse PMNs with E. coli in their interior are co-injected in the foot pad with DC, many DC loaded with fluorescent material from the PMNs reach draining lymph nodes. Using CT26 (H-2(d)) mouse tumor cells, it was observed that if tumor cells are intracellularly loaded with OVA protein and UV-irradiated, they become phagocytic prey of H-2(d) PMNs. If such PMNs, that cannot present antigens to OT-1 T cells, are immunomagnetically re-isolated and phagocytosed by H-2(b) DC, such DC productively cross-present OVA antigen determinants to OT-1 T cells. Cross-presentation to adoptively transferred OT-1 lymphocytes at draining lymph nodes also take place when OVA-loaded PMNs (H-2(d)) are coinjected in the footpad of mice with autologous DC (H-2(b)). In summary, our results indicate that antigens phagocytosed by short-lived PMNs can be in turn internalized and productively cross-presented by DC.
Autores: Suárez Fuentetaja, N.; Alfaro Alegría, C.; Dubrot Armendáriz, J.; et al.
Revista: International Journal of Cancer (Print)
ISSN 0020-7136  Vol. 129  Nº 2  2011  págs. 374 - 386
The synergy mechanism can be traced to enhanced CTLA-4 expression in effector cells as a result of T(reg) elimination, thereby offering more targets to the blocking antibody. Human T cells and allogenic DCs (derived both from healthy donors and advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-) IL-2R¿(-/-) mice. In these conditions, tremelimumab injected intravenously did not significantly enhance alloreactive proliferation unless T(reg) cells had been predepleted. Synergistic effects in vivo were again largely restricted to the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade synergistically enhanced specific cytotoxicity raised in culture against autologous EBV-transformed cell lines. Taken together, these experiments indicate that tremelimumab therapy may benefit from previous or concomitant T(reg) depletion
Autores: Alfaro, Carlos; Pérez, José Luis; et al.
Revista: The Journal of Immunology
ISSN 0022-1767  Vol. 187  Nº 11  2011  págs. 6130 - 6142
Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-alpha, TNF-alpha, and polyinosinic:polycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-gamma-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.
Autores: Sandra Hervas-Stubbs; et al.
Revista: Cancer Research
ISSN 0008-5472  Vol. 71  Nº 3  2011  págs. 801 - 11
Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag(-/-) mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies
Autores: Pérez, José Luis; Gurpide, Luis Alfonso; Ruiz-Ilundain, MG; et al.
Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
ISSN 1699-048X  Vol. 12  Nº 3  2010  págs. 174 - 180
Autores: Dubrot Armendáriz, J.; Portero, A.; Orive, G.; et al.
Revista: Cancer Immunology, Immunotherapy
ISSN 0340-7004  Vol. 59  Nº 11  2010  págs. 1621 - 1631
Autores: Milheiro, F; Alfaro, Carlos; et al.
Revista: CANCER IMMUNOLOGY IMMUNOTHERAPY
ISSN 0340-7004  Vol. 59  Nº 8  2010  págs. 1223 - 1233
Autores: Gurpide, Luis Alfonso; García-del-Barrio, MA; Pérez, José Luis;
Libro:  Manual SEOM de cuidados continuos
2014  págs. 325 - 331