Melero, I. (Ignacio)
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- Gene therapy of cancer based on interleukin 12(Bentham Science Publishers, 2005) Qian, C. (Cheng); Sangro, B. (Bruno); Melero, I. (Ignacio); Prieto, J. (Jesús)Tumor formation and growth depends mainly on the inability of the organism to elicit a potent immune response, and on the formation of new blood vessels that enable tumor nutrition. Interleukin-12 (IL-12) therapy can target both processes. And IL-12-based gene therapy may restrict IL-12 production to the relevant site in order to obtain enhanced antitumor activity and reduced toxicity. In the clinical setting, IL-12 gene transfer can be used either to improve the pharmacokinetic/pharmacodynamic profile of the cytokine, to transduce dendritic cells or to enhance the efficiency of antitumor vaccination. It can also synergize with other procedures involving the simultaneous transfer of other transgenes or non-gene based strategies. The strong anti-tumoral power shown in many different animal models has not been found in early clinical trials in which cancer patients were treated by peritumoral injections of autologous fibroblasts producing IL-12, intratumoral injections of an adenoviral vector encoding human IL-12 genes, or intratumoral injection of autologous dendritic cells transduced ex vivo with this same adenoviral vector. However, these trials have set the proof-of-concept that local production of IL-12 inside a tumor can stimulate tumor infiltration by effector immune cells and that in some cases it is followed by tumor regression. From the many questions that arise after these disappointing results the most relevant concerns the duration and intensity of transgene expression and the capability to monitor this topics in vivo. New vectors that might achieve regulated, long-term production of this cytokine might have better results and merit clinical testing.
- MAGE antigens: therapeutic targets in hepatocellular carcinoma?(Elsevier, 2004) Mazzolini, G. (Guillermo); Alfaro, C. (Carlos); Melero, I. (Ignacio); Sarobe, P. (Pablo); Feijoo, E. (Esperanza)
- Radiation effects on antitumor immune responses: current perspectives and challenges(Sage publications, 2018) Martinez-Monge, R. (Rafael); Walle, T. (Thomas); Melero, I. (Ignacio); Cerwenka, A. (Adelheid); Lecanda, F. (Fernando); Ajona, D. (Daniel)Radiotherapy (RT) is currently used in more than 50% of cancer patients during the course of their disease in the curative, adjuvant or palliative setting. RT achieves good local control of tumor growth, conferring DNA damage and impacting tumor vasculature and the immune system. Formerly regarded as a merely immunosuppressive treatment, pre- and clinical observations indicate that the therapeutic effect of RT is partially immune mediated. In some instances, RT synergizes with immunotherapy (IT), through different mechanisms promoting an effective antitumor immune response. Cell death induced by RT is thought to be immunogenic and results in modulation of lymphocyte effector function in the tumor microenvironment promoting local control. Moreover, a systemic immune response can be elicited or modulated to exert effects outside the irradiation field (so called abscopal effects). In this review, we discuss the body of evidence related to RT and its immunogenic potential for the future design of novel combination therapies.
- Adenoviral gene transfer of interleukin 12 into tumors synergizes with adoptive T cell therapy both at the induction and effector level(Mary Ann Liebert, 2000) Mazzolini, G. (Guillermo); Duarte, M. (Marina); Borras-Cuesta, F. (Francisco); Qian, C. (Cheng); Barajas, M. (Miguel); Melero, I. (Ignacio); Narvaiza, I. (Íñigo); Prieto, J. (Jesús); Xie, X. (Xiaoming)Tumors infected with a recombinant defective adenovirus expressing interleukin 12 (IL-12) undergo regression, associated with a cytotoxic T lymphocyte (CTL)-mediated antitumor immune response. In the present study we generated anti-CT26 CTLs by short-term coculture of CT26 cells and lymph node cells obtained from mice harboring subcutaneous CT26 tumors injected with an adenoviral vector expressing IL-12 (AdCMVIL-12), control adenovirus (AdCMVlacZ), or saline. Regression of small intrahepatic CT26 tumors in unrelated syngeneic animals was achieved with CTLs derived from mice whose subcutaneous tumors had been injected with AdCMVIL-12 but not with CTLs from the other two control groups. The necessary and sufficient effector cell population for adoptive transfer consisted of CD8+ T cells that showed anti-CT26 specificity partly directed against the AH1 epitope presented by H-2Ld. Interestingly, treatment of a subcutaneous tumor nodule with AdCMVIL-12, combined with intravenous adoptive T cell therapy with short-term CTL cultures, had a marked synergistic effect against large, concomitant live tumors. Expression of IL-12 in the liver in the vicinity of the hepatic tumor nodules, owing to spillover of the vector into the systemic circulation, appeared to be involved in the increased in vivo antitumor activity of injected CTLs. In addition, adoptive T cell therapy improved the outcome of tumor nodules transduced with suboptimal doses of AdCMVIL-12. Our data provide evidence of a strong synergy between gene transfer of IL-12 and adoptive T cell therapy. This synergy operates both at the induction and effector phases of the CTL response, thus providing a rationale for combined therapeutic strategies for human malignancies.
- Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15(Taylor & Francis, 2018) Berraondo, P. (Pedro); Gomar, C. (Celia); Etxeberria, I. (Iñaki); Perez-Ruiz, E. (Elisabeth); Rodriguez, I. (Inmaculada); Mayer, J.P. (Jan Peter); Garasa, S. (Saray); Inoges, S. (Susana); Lopez, A. (Ascensión); Ochoa, M.C. (María Carmen); Melero, I. (Ignacio); Vasquez, M. (Marcos); Wirtz, P. (Peter); Minute, L. (Luna)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 IL15Rα, 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-/-γc-/- 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.
- Short-term local expression of a PD-L1 blocking antibody from a self-replicating RNA vector induces potent antitumor responses(2019) Kochan, G. (Grazyna); Mancheño, U. (Uxua); Sanchez-Paulete, A.R. (Alfonso R.); Smerdou, C. (Cristian); Galindo, J. (Javier); Ballesteros-Briones, M.C. (María Cristina); Hervas-Stubbs, S. (Sandra); Melero, I. (Ignacio); Casales, E. (Erkuden); Prieto, J. (Jesús); Martisova, E. (Eva); Gorraiz, M. (Marta); Escors, D. (David); Hernandez-Alcoceba, R. (Rubén); Buñuales, M. (María); Silva-Pilipich, N.R. (Noelia Romina); Lasarte, J.J. (Juan José)Immune checkpoint blockade has shown anti-cancer efficacy, but requires systemic administration of monoclonal antibodies (mAbs), often leading to adverse effects. To avoid toxicity, mAbs could be expressed locally in tumors. We developed adeno-associated virus (AAV) and Semliki Forest virus (SFV) vectors expressing anti-programmed death ligand 1 (aPDL1) mAb. When injected intratumorally in MC38 tumors, both viral vectors led to similar local mAb expression at 24 h, diminishing quickly in SFV-aPDL1-treated tumors. However, SFV-aPDL1 induced >40% complete regressions and was superior to AAV-aPDL1, as well as to aPDL1 mAb given systemically or locally. SFV-aPDL1 induced abscopal effects and was also efficacious against B16-ovalbumin (OVA). The higher SFV-aPDL1 antitumor activity could be related to local upregulation of interferon-stimulated genes because of SFV RNA replication. This was confirmed by combining local SFV-LacZ administration and systemic aPDL1 mAb, which provided higher antitumor effects than each separated agent. SFVaPDL1 promoted tumor-specific CD8 T cells infiltration in both tumor models. In MC38, SFV-aPDL1 upregulated co-stimulatory markers (CD137/OX40) in tumor CD8 T cells, and its combination with anti-CD137 mAb showed more pronounced antitumor effects than each single agent. These results indicate that local transient expression of immunomodulatory mAbs using non-propagative RNA vectors inducing type I interferon (IFN-I) responses represents a potent and s
- Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma(2020) Yau, T. (Thomas); El-Khoueiry, A. (Anthony); Tang, H.T. (Hao Tracy); Park, J.W. (Joong-Won); Boyd, Z. (Zachary); Shen, Y. (Yun); Furuse, J. (Junji); Wadhawan, S. (Samir); Sangro, B. (Bruno); Neely, J. (Jaclyn); Melero, I. (Ignacio); Tschaika, M. (Marina); Finn, R.S. (Richard S.); Cheng, A.L. (Ann-Lii); Abou-Alfa, G.K. (Ghassan K.)Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1-positive and PD-L1-negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2-n.a.) vs. 16.6 months (95% CI 14.2-20.2) for patients with tumour PD-L1 >= 1% vs. <1% (p = 0.03). Increased CD3 and CD8 showed a non-significant trend towards improved OS (both p = 0.08), and macrophage markers were not associated with OS. Tumour PD-1 and PD-L1 expression were associated with improved OS (p = 0.05 and p = 0.03, respectively). An inflammatory gene signature consisting of 4 genes was associated with improved objective response rate (p = 0.05) and OS (p = 0.01). Conclusions: PD-1 and PD-L1 expression, biomarkers of inflammation, and inflammatory gene signatures trended with improved survival and response. While further confirmation within a larger phase III trial is needed to evaluate predictive value of these biomarkers, these exploratory analyses suggest that anti-tumour immune response may play a role in the treatment benefit of nivolumab in HCC. Lay summary: Certain tests may be used to provide a picture of how a tumour is escaping the immune system, allowing it to continue to grow and create more tumours. Therapies such as nivolumab are designed to help the immune system fight the tumour. These tests may be used to determine how effective such therapies will be in the treatment of advanced liver cancer. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.
- Interleukin-12 message in a bottle(American Association for Cancer Research, 2020) Berraondo, P. (Pedro); Cirella, A. (Assunta); Di-Trani, C.A. (Claudia Augusta); Melero, I. (Ignacio)IL12 is a very potent cancer immunotherapy agent, but is difficult to harness safely if given systemically. Local gene transfer aims to confine the effects of IL12 to malignant tissues, thus avoiding toxicity. Lipid-nanoparticle mRNA achieves IL12 expression and efficacy in mouse models, opening the way to an ongoing trial.
- Quantitative and qualitative impairments in dendritic cell subsets of patients with ovarian or prostate cancer(Elsevier, 2020) Monique-de-Vries, I.J. (Ingrid Jolanda); Mastelic-Gavillet, B. (Beatris); Kandalaft, L.E. (Lana E.); Vigano, S. (Selena); Coukos, G. (George); Jichlinski, P. (Patrice); Lozano, L.E. (Leyder Elena); Derre, L. (Laurent); Harari, A. (Alexandre); Romero, P.J. (Pedro J.); Dartiguenave, F. (Florence); Inoges, S. (Susana); Melero, I. (Ignacio); Wyss, T. (Tania); Sarivalasis, A. (Apostolos)Background Dendritic cells (DCs) are the most efficient antigen-presenting cells, hence initiating a potent and cancer-specific immune response. This ability (mainly using monocyte-derived DCs) has been exploited in vaccination strategies for decades with limited clinical efficacy. Another alternative would be the use of conventional DCs (cDCs) of which at least three subsets circulate in human blood: cDC1s (CD141bright), cDC2s (CD1c+) and plasmacytoid DCs. Despite their paucity, technical advances may allow for their selection and clinical use. However, many assumptions concerning the DC subset biology depend on observations from mouse models, hindering their translational potential. In this study, we characterise human DCs in patients with ovarian cancer (OvC) or prostate cancer (PrC). Patients and methods Whole blood samples from patients with OvC or PrC and healthy donors (HDs) were evaluated by flow cytometry for the phenotypic and functional characterisation of DC subsets. Results In both patient groups, the frequency of total CD141+ DCs was lower than that in HDs, but the cDC1 subset was only reduced in patients with OvC. CD141+ DCs showed a reduced response to the TLR3 agonist poly (I:C) in both groups of patients. An inverse correlation between the frequency of cDC1s and CA125, the OvC tumour burden marker, was observed. Consistently, high expression of CLEC9A in OvC tissue (The Cancer Genome Atlas data set) indicated a better overall survival. Conclusions cDC1s are reduced in patients with OvC, and CD141+ DCs are quantitatively and qualitatively impaired in patients with OvC or PrC. CD141+ DC activation may predict functional impairment. The loss of cDC1s may be a bad prognostic factor for patients with OvC.
- Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies(Elsevier, 2020) García-Aranda, M. (Marilina); Perez-Ruiz, E. (Elisabeth); Sarmento-Ribeiro, A.B. (Ana Bela); Melero, I. (Ignacio); Kopecka, J. (Joanna); De-las-Rivas, J. (Javier)Cancer is one of the main public health problems in the world. Systemic therapies such as chemotherapy and more recently target therapies as well as immunotherapy have improved the prognosis of this large group of complex malignant diseases. However, the frequent emergence of multidrug resistance (MDR) mechanisms is one of the major impediments towards curative treatment of cancer. While several mechanisms of drug chemoresistance are well defined, resistance to immunotherapy is still insufficiently unclear due to the complexity of the immune response and its dependence on the host. Expression and regulation of immune checkpoint molecules (such as PD-1, CD279; PD-L1, CD274; and CTLA-4, CD152) play a key role in the response to immunotherapy. In this regard, immunotherapy based on immune checkpoints inhibitors (ICIs) is a common clinical approach for treatment of patients with poor prognosis when other first-line therapies have failed. Unfortunately, about 70 % of patients are classified as non-responders, or they progress after initial response to these ICIs. Multiple factors can be related to immunotherapy resistance: characteristics of the tumor microenvironment (TME); presence of tumor infiltrating lymphocytes (TILs), such as CD8 + T cells associated with treatment-response; presence of tumor associated macrophages (TAMs); activation of certain regulators (like PIK3γ or PAX4) found present in non-responders; a low percentage of PD-L1 expressing cells; tumor mutational burden (TMB); gain or loss of antigen-presenting molecules; genetic and epigenetic alterations correlated with resistance. This review provides an update on the current state of immunotherapy resistance presenting targets, biomarkers and remedies to overcome such resistance.