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Ascensión López Díaz de Cerio

Publicaciones científicas más recientes (desde 2010)

Autores: López Díaz de Cerio, Ascensión; Garcia-Munoz, R.; Pena Carbó, Esther; et al.
ISSN 0007-1048  Vol. 189  Nº 6  2020  págs. 1064 - 1073
Anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post-induction therapy, by enhancing antibody-dependent cellular cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised thatex vivoexpanded lymphokine-activated killer (LAK) cells administered to FL-remission patients are safe and improve anti-CD20 efficacy. This open, prospective, phase II, single-arm study assessed safety and efficacy ofex vivoexpanded LAK cells in 20 FL-remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL-2) for 8 weeks, after which >5 x 10(8)LAK cells were injected. Patients were followed-up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL-2 (rhIL-2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment-related serious adverse events. Three patients had progressed by the end of follow-up. After a median (interquartile range) follow-up of 59.4 (43.8-70.9) months, 85% of patients remained progression free. No deaths occurred. Quality-of-life improved throughout the study. Post-induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.
Autores: Urrizola Martínez, Amaia; Pérez Solans, Belén; Sánchez Bayona, Rodrigo; et al.
ISSN 0923-7534  Vol. 31  2020  págs. S710 - S710
Autores: Ochoa Nieto, Maria del Carmen; Perez-Ruiz, E.; Minute, L. ; et al.
ISSN 2162-402X  Vol. 8  Nº 7  2019  págs. 1599636
Daratumumab is an anti-CD38 fully human IgG1 mAb approved for multiple myeloma treatment. One of the proposed mechanisms of action is the induction of antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells. NK cells acquire surface CD137 expression in the presence of solid-phase-attached daratumumab and when encountering a daratumumab-coated CD38(+) tumor cell line. In this setting, addition of the agonist anti-CD137 mAb urelumab enhances NK-cell activation increasing CD25 expression and IFN gamma production. However, in vitro ADCC is not increased by the addition of urelumab both in 4h or 24h lasting experiments. To study urelumab-increased daratumumab-mediated ADCC activity in vivo, we set up a mouse model based on the intravenous administration of a luciferase-transfected multiple myeloma cell line of human origin, human NK cells and daratumumab to immuno-deficient NSG mice. In this model, intravenous administration of urelumab 24h after daratumumab delayed tumor growth and prolonged mice survival.
Autores: Willekens, B.; Presas-Rodríguez, S. ; Mansilla, M. J. ; et al.
Revista: BMJ OPEN
ISSN 2044-6055  Vol. 9  Nº 9  2019  págs. e030309
Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. Methods and analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. Ethics and dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. Trial registration numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.
Autores: Solans, B. P.; López Díaz de Cerio, Ascensión; Elizalde Pérez, Arlette María; et al.
ISSN 0306-5251  Vol. 85  Nº 8  2019  págs. 1670 - 1683
AimsImmunotherapy is a rising alternative to traditional treatment in breast cancer (BC) patients in order to transform cold into hot immune enriched tumours and improve responses and outcome. A computational modelling approach was applied to quantify modulation effects of immunotherapy and chemotherapy response on tumour shrinkage and progression-free survival (PFS) in naive BC patients. MethodsEighty-three Her2-negative BC patients were recruited for neoadjuvant chemotherapy with or without immunotherapy based on dendritic cell vaccination. Sequential tumour size measurements were modelled using nonlinear mixed effects modelling and linked to PFS. Data from another set of patients (n=111) were used to validate the model. ResultsTumour size profiles over time were linked to biomarker dynamics and PFS. The immunotherapy effect was related to tumour shrinkage (P < .05), with the shrinkage 17% (95% confidence interval: 2-23%) being higher in vaccinated patients, confirmed by the finding that pathological complete response rates in the breast were higher in the vaccinated compared to the control group (25.6% vs 13.6%; P=.04). The whole tumour shrinkage time profile was the major prognostic factor associated to PFS (P < .05), and therefore, immunotherapy influences indirectly on PFS, showing a trend in decreasing the probability of progression with increased vaccine effects. Tumour subtype was also associated with PFS (P < .05), showing that luminal A BC patients have better prognosis. ConclusionsDendritic cell-based immunotherapy is effective in decreasing tumour size. The semi-mechanistic validated model presented allows the quantification of the immunotherapy treatment effects on tumour shrinkage and establishes the relationship between the dynamics of tumour size and PFS.
Autores: Yuste Ara, José Ramón (Autor de correspondencia); López Díaz de Cerio, Ascensión; Rifón Roca, José Juan; et al.
ISSN 1359-6535  Vol. 24  Nº 4  2019  págs. 313 - 319
Cytomegalovirus (CMV) infections can induce severe complications in immunosuppressed patients. Currently, ganciclovir represents the preferred treatment option; however, in patients with resistance or toxicity related to ganciclovir, the therapeutic options are limited. Cellular immunity plays an important role in the control of viral infections. Adoptive T-cell therapy can contribute to recovering immunological function in immunosuppressed patients. Selective T-cell depletion targeting CD45RA enhances early T-cell recovery and can represent a salvage therapy. In this study, an immunocompromised non-transplanted patient with CMV disease and toxicity to conventional therapy was successfully treated by adoptive transfer of CD45RA-depleted T-cells.
Autores: Schalper, K. A. ; Rodriguez-Ruiz, M. E.; Diez Valle, Ricardo; et al.
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: Pena Carbó, Esther; Munoz, R. G.; López Díaz de Cerio, Ascensión; et al.
ISSN 0390-6078  Vol. 104  2019  págs. 3 - 4
Autores: Presas-Rodriguez, S. ; Willekens, B.; Mansilla, M. J.; et al.
ISSN 0028-3878  Vol. 92  Nº 15 Supl.  2019 
Autores: Rodríguez Ruiz, María Esperanza; Pérez Gracia, José Luis; Rodríguez, I.; et al.
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: Rodríguez Rodríguez, Javier; Castañón Álvarez, Eduardo; Pérez Gracia, José Luis; et al.
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: Ochoa Nieto, Maria del Carmen; Cordeiro Minute, Luna Ridan; López Díaz de Cerio, Ascensión; et al.
ISSN 2162-402X  Vol. 7  Nº 2  2018  págs. e1393597
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15R alpha, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8(+) T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8(+) T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo. The EGFR(+) human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2(gamma)(-/-)c(-/-) mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1(-/-) mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens.
Autores: Pelacho Samper, Beatriz; López Díaz de Cerio, Ascensión; Inoges Sancho, Susana Inmaculada; et al.
ISSN 0195-668X  Vol. 39  Nº Supl. 1  2018  págs. 1196 - 1196
Autores: Esparragosa Vázquez, Inés; Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; et al.
ISSN 1522-8517  Vol. 20  Nº Supl. 3  2018  págs. 243 - 243
Autores: Willekens, B.; Presas-Rodriguez, S. ; Mansilla, M.; et al.
ISSN 1352-4585  Vol. 24  Nº 2_suppl: P1202  2018  págs. 530 - 737
Objectives: To assess the clinical use of tolDC in a well-defined population of MS patients in two single-center clinical trials, comparing two ways of tolDC administration, namely intradermal (i.d.) (MS-tolDC, Antwerp) and intranodal (i.n.) (TOLERVIT-MS, Badalona). Aims: To demonstrate safety and feasibility of therapeutic use of tolDC in MS patients.
Autores: Muntasell, A.; Ochoa Nieto, Maria del Carmen; Cordeiro, L.; et al.
ISSN 0952-7915  Vol. 45  2017  págs. 73 - 81
Natural Killer (NK) cells are cytotoxic lymphocytes specialized in early defense against virus-infected and transformed cells. NK-cell function is regulated by activating and inhibitory surface receptors recognizing their ligands on transformed cells. Modulation of NK numbers and/or function by a variety of agents such as cytokines and monoclonal antibodies may result in enhanced anti-tumor activity. Recombinant cytokines (i.e., IL-15 and IL-2), antibodies blocking inhibitory receptors (i.e., KIR, NKG2A and TIGIT) and agonists delivering signals via CD137, NKG2D and CD16 stand out as the most suitable opportunities. These agents can be used to potentiate NKcell- mediated antibody-dependent cellular cytotoxicity (ADCC) against antibody-coated tumor cells, offering potential for multiple combinatorial immunotherapy strategies against cancer.
Autores: Martínez Soldevilla, Mario; Hervas Stubbs, Sandra; Villanueva Ruiz, Helena; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 12  Nº 9  2017  págs. e0185169
LAG3 receptor belongs to a family of immune-checkpoints expressed in T lymphocytes and other cells of the immune system. It plays an important role as a rheostat of the immune response. Focus on this receptor as a potential therapeutic target in cancer immunotherapy has been underscored after the success of other immune-checkpoint blockade strategies in clinical trials. LAG3 showcases the interest in the field of autoimmunity as several studies show that LAG3-targeting antibodies can also be used for the treatment of autoimmune diseases. In this work we describe the identification of a high-affinity LAG3 aptamer by High Throughput Sequencing SELEX in combination with a study of potential conserved binding modes according to sequence conservation by using 2D-structure prediction and 3D-RNA modeling using Rosetta. The aptamer with the highest accumulation of these conserved sequence motifs displays the highest affinity to LAG3 recombinant soluble proteins and binds to LAG3-expressing lymphocytes. The aptamer described herein has the potential to be used as a therapeutic agent, as it enhances the threshold of T-cell activation. Nonetheless, in future applications, it could also be engineered for treatment of autoimmune diseases by target depletion of LAG3-effector T lymphocytes.
Autores: Inoges Sancho, Susana Inmaculada; Tejada Solís, Sonia; López Díaz de Cerio, Ascensión; et al.
ISSN 1479-5876  Vol. 15  Nº 1  2017  págs. Article number 104
Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival. Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were finally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meier method. Immune response were assessed in blood samples obtained before each vaccines. Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufficient resection. Median age was 61 years (range 42-70). Karnofsky performance score (KPS) was 90-100 in 29%, 80 in 35.5% and 60-70 in 35.5% of cases. MGMT (O6-methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse effects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7-16) and median OS was 23.4 months (95% CI 16-33.1). Increase in post-vaccination tumor specific immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correlation between immune response and survival was found. Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and Identifier: NCT01006044 retrospectively registered.
Autores: Baraibar Argota, Iosune; Martín Romano, Patricia; Mejías Sosa, Luis Daniel; et al.
ISSN 0008-5472  Vol. 77  Nº 4 Supl.  2017  págs. P2-04-01
Autores: Lord, P., (Autor de correspondencia); Spiering, R.; Aguillon, J. C.; et al.
Revista: PEERJ
ISSN 2167-8359  Vol. 4  2016  págs. e2300
Cellular therapies with tolerogenic antigen-presenting cells (tolAPC) show great promise for the treatment of autoimmune diseases and for the prevention of destructive immune responses after transplantation. The methodologies for generating tolAPC vary greatly between different laboratories, making it difficult to compare data from different studies; thus constituting a major hurdle for the development of standardised tolAPC therapeutic products. Here we describe an initiative by members of the tolAPC field to generate a minimum information model for tolAPC (MITAP), providing a reporting framework that will make differences and similarities between tolAPC products transparent. In this way, MITAP constitutes a first but important step towards the production of standardised and reproducible tolAPC for clinical application.
Autores: Martínez Soldevilla, Mario; Villanueva Ruiz, Helena; Casares Lagar, Noelia; et al.
ISSN 1949-2553  Vol. 7  Nº 17  2016  págs. 23182 - 23196
In this work we show a clinically feasible strategy to convert in situ the own tumor into an endogenous vaccine by coating the melanoma cancerous cells with CD28 costimulatory ligands. This therapeutic approach is aimed at targeting T-cell costimulation to chemotherapy-resistant tumors which are refractory and been considered as untreatable cancers. These tumors are usually defined by an enrichment of cancer stem cells and characterized by the higher expression of chemotherapy-resistant proteins. In this work we develop the first aptamer that targets chemotherapy-resistant tumors expressing MRP1 through a novel combinatorial peptide-cell SELEX. With the use of the MRP1 aptamer we engineer a MRP1-CD28 bivalent aptamer that is able to bind MRP1-expressing tumors and deliver the CD28 costimulatory signal to tumor-infiltrating lymphocytes. The bi-specific aptamer is able to enhance costimulation in chemotherapy-resistant tumors. Melanoma-bearing mice systemically treated with MRP1-CD28 bivalent aptamer show reduced growth, thus proving an improved mice survival.Besides, we have designed a technically feasible and translational whole-cell vaccine (Aptvax). Disaggregated cells from tumors can be directly decorated with costimulatory ligand aptamers to generate the vaccine Aptvax. CD28Aptvax made of irradiated tumor cells coated with the CD28-agonistic aptamer attached to MRP1 elicits a strong tumor- cell immune response against melanoma tumors reducing tumor growth.
Autores: García-Muñoz, R.; López Díaz de Cerio, Ascensión; Feliu, J.; et al.
ISSN 0257-277X  Vol. 64  Nº 2  2015  págs. 548-57
Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.
Autores: Martínez Soldevilla, Mario; Villanueva Ruiz, Helena; Bendandi, Maurizio; et al.
ISSN 0142-9612  Vol. 67  2015  págs. 274 - 285
Recent studies have underscored the importance of immunomodulatory antibodies in the treatment of solid and hematological tumors. ODN-Aptamers are rising as a novel class of drugs that can rival therapeutic antibodies. The success of some of the current cancer immunotherapy approaches in oncological patients depends on the intrinsic antigenicity of each tumor as has recently been disclosed, and it is hampered in those patients that are treated with myeloablative chemotherapy or radiotherapy, which induce profound immunosuppression. CD40 agonist and antagonist molecules offer a new therapeutic alternative which has the potential to generate anticancer effects by different mechanisms. HS-SELEX was performed to identify high-affinity aptamers against CD40, and three therapeutic CD40 constructs were engineered as: CD40 agonist aptamer, CD40 antagonist aptamer and CD40 agonistic aptamer-shRNA chimera. It is shown that CD40 agonist aptamers can be used to promote bone-marrow aplasia recovery. CD40 antagonist aptamers are revealed to have a direct antitumor effect on CD40-expressing B-cell lymphoma in vitro and in vivo. Further, in order to identify a therapeutic reagent that will generate the optimal conditions for cancer immunotherapy (antigen-presenting cell activation, tumor antigenicity enhancement and bone-marrow aplasia recovery), CD40 agonist aptamer-shRNA chimera was generated to target the inhibition of the Nonsense mRNA Mediated Decay (NMD) to tumor cells.
Autores: Tusé D.; Ku,N.; Bendandi, Maurizio; et al.
ISSN 2314-6133  Vol. 2015  2015  págs. 648143 - 648143
We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ¿6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ¿4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Villanueva Ruiz, Helena; et al.
ISSN 1064-3745  Vol. 1139  2014  págs. 367-87
Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy both in Europe and in the United States. Follicular lymphoma (FL), a tumor comprised of mature B cells, represents one fourth of all NHL and, despite good response rates to standard treatments, tends to frequently relapse to such an extent that it is still considered incurable. Among several alternative therapeutic options actively being pursued, immunotherapy by idiotypic vaccination is in the forefront of clinical experimental medicine. The idiotype vaccine consists of the tumor-specific immunoglobulin conjugated with keyhole limpet hemocyanin (KLH) and administered together with an adjuvant. Over the last 20 years, researchers have proven that this vaccine can induce specific immune responses. Too, those patients with such responses experience a disease-free survival longer than normally achievable, although these latter results require further confirmation in large clinical trials. Traditionally, idiotype vaccines have been produced through hybridoma technology. In this chapter this technology is described.
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Villanueva Ruiz, Helena; et al.
ISSN 0065-230X  Vol. 2013  2013  págs. 1-13
diotypic vaccination for folicular lymphoma induces a tumor-specific immune response which may kill tumor cells in vivo and prevent tumor relapse in patients. However, being based on a personalized vaccine against a person¿s own tumor, large scale randomized studies have produced contradictory results. The objective of this review is to define what an idiotype is and to outline the major results of twenty years of clinical research on idiotypic vaccination. We first identified the major proofs of principle obtained by its use between 1992 and 2006, focusing on both our and others¿ contributions. Then, we analyzed the results of randomized clinical trials, which have become available ove the last five years, and provided some of our most recent and original data. A combination of immunological methods should be employed for proper interpretation of immune response following idiotypic vaccination. We describe some of the methods used to measure immune responses and identify tumor idiotype sequences. Some of the older methods (e.g. ELISA) may, in some instances, be misleading, and should be validated using different methods (e.g. flow cytometry). Moreover, patients who relapse years after the end of the vaccination schedule, may have undergone changes in tumor idiotype tumor idiotypes that have undergone substantial changes and is advisable to test the tumor clone at relapse to ascertain it. While idiotypic vaccination has provided proof-of-principle of effectiveness, the data
Autores: López Díaz de Cerio, Ascensión; Inoges Sancho, Susana Inmaculada; Ai WZ; et al.
ISSN 1029-2403  Vol. 54  Nº 4  2013  págs. 881-884
Autores: Diez Valle, Ricardo; López Díaz de Cerio, Ascensión; Inoges Sancho, Susana Inmaculada; et al.
ISSN 2218-4333  Vol. 3  Nº 11  2012  págs. 142-149
Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results.
Autores: Castillo Andueza, Ainhoa; Salgado Pascual, José Esteban; Inoges Sancho, Susana Inmaculada; et al.
ISSN 0008-5472  Vol. 72  Nº Sup.24  2012 
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Villanueva Ruiz, Helena; et al.
ISSN 1476-0584  Vol. 10  Nº 6  2011  págs. 801-9
Despite having been the first cancer vaccine to provide clear-cut evidence of biological and clinical efficacy as well as of clinical benefit in humans, idiotype vaccines have failed to become the first therapeutic cancer vaccine to be granted regulatory approval. Indeed, idiotypic vaccination is still an experimental therapeutic option for some types of B-cell malignancy over 20 years after its first use in patients with lymphoma. The ultimate reason for this situation lies in the recent failure of three large-scale, independent, randomized trials to achieve their respective main clinical end points. Interestingly, each trial had been designed with intrinsic pitfalls that are likely to have influenced, and perhaps even entirely compromized, all chances each study had to succeed. Therefore, it is difficult to conclude whether any of the different idiotype vaccines employed so far may still represent an ideal candidate for further trials. Meanwhile, other idiotype vaccine formulations are under active investigation.
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Sampol A; et al.
ISSN 1568-0266  Vol. 11  Nº 13  2011  págs. 1653-60
Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Villanueva Ruiz, Helena; et al.
ISSN 2218-4333  Vol. 2  Nº 6  2011  págs. 237-244
Over the last two decades, lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand, as well as clinical benefit on the other. More recently, however, three large-scale, independent, randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial's study design than on each vaccination strategy per se. Independently of these considerations, a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that, even to date, no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced, idiotype-specific immune as well as clinical responses. The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.
Autores: Villanueva, H.; López Díaz de Cerio, Ascensión; Inoges Sancho, Susana Inmaculada; et al.
ISSN 1476-0584  Vol. 10  Nº 12  2011  págs. 1661 - 1669
Most patients with B-cell lymphoma face an often incurable disease, particularly those diagnosed with an indolent subtype. The addition of passive immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. However, a cure remains elusive in most cases. For this reason, the patient-and tumor-specific idiotype, that is the collection of epitopes exclusively presented by the tumor clone's surface immunoglobulin, has been extensively studied as a privileged target for vaccine therapy, aiming at preventing disease re-occurrence after standard treatment. BiovaxID (R) (Biovest International, FL, USA), the most clinically advanced among such therapeutic vaccines, finds itself at a crucial turning point when it comes to further development. Both clinical trials in which it has been formally employed have shown intriguing results. Independent studies using slightly different versions of a conceptually identical vaccine provided all proofs of principle required to ascertain the vaccine's value - biological and clinical efficacy as well as clinical benefit. However, all these data have failed to bring an idiotype vaccine to the market owing to reasons that often have very little to do with the product itself. In fact, some successful studies were not conceived with this goal in mind, while others simply did not enroll enough patients to convincingly make their case for regulatory ap
Autores: Inoges Sancho, Susana Inmaculada; López Díaz de Cerio, Ascensión; Soria Saldise, Elena; et al.
ISSN 1381-6128  Vol. 16  Nº 3  2010  págs. 300-7
After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines.
Autores: Bendandi, Maurizio; Marillonnet S; Kandzia R; et al.
ISSN 0923-7534  Vol. 21  Nº 12  2010  págs. 2420-7
This manufacturing process is reliable and robust, the manufacturing time from biopsy to vaccine is <12 weeks and the expression and purification of antigens require only 2 weeks. The process is also broadly applicable for manufacturing monoclonal antibodies in plants, providing 50- to 1000-fold higher yields than alternative plant expression methods.