WP3. New immunodepleting and immunomodulating strategies with broader indications and enhanced efficacy
The IGO teams have already been implementing immunotherapeutic approaches that aim at boosting antitumor adaptive immunity and inflammatory responses (eg with antitumor vaccines, T cell agonists, transferred DC or IL15 agonists), at inducing immunosuppression towards allogeneic cells (eg with CD28 antagonists or tolerogenic DCs), and at promoting clearance of tumor or deleterious immune cells (eg with Ab against CD20, CD138, CD115 or IL17-R). Although promising preclinical or clinical responses have been achieved, the immunotherapeutic efficacy of these approaches is far from being optimal and needs to be improved. To this end, WP3 will encompass two projects that aim at identifying new markers for improved selection of eligible patients (P6), and designing optimized depleting or immumodulating protocols with broad indications. (i) Within project P6, IGO will study how manipulation of apoptosis in two seemingly different paradigms (i.e. tumor growth and organ transplantation) could enhance the efficacy of current therapies or provide a rationale for new combinations for radio-or chemo‐hanced immunotherapies. This will be done through molecular profiling of death susceptibility of cancer and immune cells in response to immuno-, chemo-or radiotherapy in vitro and ex vivo, and design of new approaches for in vivo imaging of cell apoptosis. (ii) Within project P7, IGO will develop new immunotherapies with enhanced efficacy in transplantation and oncology, through improvement of Ab-based depletion of tumor cells, immunosuppressive or effector immune subsets by radiotargeting and large scale screening of various combination strategies involving immunostimulating or immunosuppressive reagents. Strategies combining apoptogens (eg Bcl inhibitors) and immunotherapeutic agents (eg anti-CD28) will be also assessed, as well as innovative depleting approaches using new technological platforms (nanofitins, affibodies).
Task 6 – Apoptosis and Immunity
Task 6.1 “Cancer cell death and modulation of the tumoral niche”
The goal of this project is to study the influence of cancer cell death induced by chemo- and/or radio- therapies on the tumoral niche functions. A special emphasis will be on the modification of cellular phenotypes through changes in epigenetic modifications of lymphocytes, macrophages and endothelial cells. Most of the work will be performed with primary cultures obtained from patients with glioblastoma multiforme, the major brain tumors in adult. We will used in vitro and in vivo (xenografts) analyses to study the consequences of classical treatments (i.e. temozolomide + irradiation) on the different populations that compose the tumor. We will also explore the modification of the niche by the different components released during cancer cell death (i.e. metabolites, lipids, ATP…). We will focus in particular on prostaglandin and TMZ induced signaling, epigenetic and metabolic changes in immune and cancer cells on EGFR and apoptosis pathways. The aim of this study is to provide new targets and therapeutic options for the deadly brain tumors.
Task 7 – “Innovative strategies to enhance the efficacy of immunomodulating and immunodepleting therapies”
Task 7.1 CD138 Radiotargeting and Immunostimulation
Multiple myeloma (MM) is an incurable hematological pathology resulting from the malignant transformation of a plasmocyte accumulating in bone marrow and that can potentially invade extramedullary sites in advanced stages of the disease. MM represents approximately 1% of all cancers and 10% of malignant hemopathies. During the last decade, new treatments have significantly improved the median survival of patients. However, the development of innovative and efficient therapeutic approaches remains a necessity.
Ionizing radiations are largely used to eradicate cancer cells by a direct cytotoxicity, potentially associated with a bystander effect. Although often considered as immunosuppressive, numerous studies have shown that radiotherapy can have an impact on the tumor at distance from the field of irradiation that is mediated by the immune system. In MM patients, ionizing radiations can be delivered to tumor cells by radioimmunotherapy (RIT), a new approach of internal targeted radiotherapy using tumor antigen specific monoclonal antibodies coupled to radioactive atoms.
The goal of this project is to study the relevance of combining RIT with different immunotherapies in a murine myeloma model. RIT will specifically target the tumor cells with an antibody coupled to beta or alpha radionuclides. Stimulation of the immune system will be done either by an interleukin-15 agonist (RLI), by vaccination with tumor antigen coupled to carrier proteins or by adoptive transfer of tumor specific T lymphocytes. This preclinical study shall open interesting therapeutic perspectives in the context of MM that could potentially extend to other malignant pathologies. Indeed, the possibility to raise an anti-tumor immune response with RIT combined to different immune-based strategies would provide the advantage to set up an immunologic memory that could benefit the patient facing a cancer recurrence and to adapt to the genomic instability of tumor cells.
Task 7.2 – Enhancing the efficacy of anti-cancer vaccines using immunostimulants or/and inhibition of immunosuppression
Immunotherapy approaches based on well-characterized tumor antigens is emerging as a powerful strategy for the elicitation or reinforcement of tumor specific immune responses. Their clinical efficacy, however, is limited by the often modest immunogenicity of tumor antigens and by the existence of immunoregulatory mechanisms that limit the onset or/and amplification of tumor specific immune responses. These limitations can be in principle overcome by the use, separately or in combination, of immunostimulatory molecules or/and strategies for the inhibition of immunosuppression, provided that suitable pre-clinical models for the selection of the more promising molecules are available.
With the aim of developing such a model, we have recently implemented a versatile in vitro platform for the priming of CD4 T cells specific for the human tumor antigen NY-ESO-1, of the Cancer Testis group, presently one of the most promising candidates for the development of human anti-cancer vaccines (Poli C. et al Heamatologica 2013, 98:316-22).
In this project, we will exploit this in vitro priming system to assess immunostimulatory agents (γδ T cell agonists, hyper-IL-15) or/and those that are candidate to interfere with immunosuppressive mechanisms (inhibitors of CD115, prostaglandin inhibitors). This simple but efficient strategy will allow the rapid screening of the candidate active molecules most promising for clinical development.
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