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Renforcement des effets immunomodulateurs d’un anticorps monoclonal anti-tumoral : étude des effets potentialisateurs de thérapies combinées et analyse des mécanismes impliqués

Abstract : Melanoma is the most aggressive form of skin cancer. Although early management is of good prognosis, the survival of patients decrease dramatically for metastatic stages. Despite the recent spectacular therapeutic advances, the major problem lies in resistance to treatment and relapse and the main challenge now is to develop an effective and sustainable control. Monoclonal antibodies (mAbs) have the ability to specifically target and eliminate tumor cells while recruiting cells from the immune system, to develop and / or enhance the immunity of the host with the development of a vaccinal immune response. In a solid tumor model of murine melanoma after subcutaneous transplantation of B16F10 cells, we investigated the immunomodulatory effect of TA99 mAb targeting a TYRP-1 surface antigen overexpressed in tumor melanocytes. Our results showed that about 30% of mice are protected in the long term and have an antitumoral humoral and cellular immune response. Moreover, the analysis of the immune infiltrate in mice that escape to the treatment with TA99 mAb and develop a tumor, shows an overexpression of PD-1 and Tim3 associated with a loss of effector cell functions within the tumor. This same phenotype has been observed in biopsies of patients with metastatic melanoma. Thus, blocking the PD-1 / PDL-1 axis by inoculation of an anti-PD1 mAb at the time of tumor escape potentiates the anti-tumor immune response and results in increased survival. However, the absence of complete regression suggests the establishment of other immunosuppressive pathways. Indeed we have observed an overexpression of CD39 and CD73 ectonucleotidases in the tumor microenvironment suggesting the involvement of adenosine in the resistance mechanisms observed and opening interesting perspectives for the concomitant blocking of this pathway and the PD1 / PDL-1 axis. Another strategy has been to improve the early immunomodulatory effects of TA99 mAb by combining it with oxaliplatin, a chemotherapy that promotes immunogenic death. Although the therapeutic combinations tested in this study showed encouraging in vivo effects with a significant delay in overall survival, no significant increase in the long-term anti-tumor response was observed, suggesting the establishment of other non-redundant immunosuppressive mechanisms or unsuitable combinations strategies. Both phenotypic and functional analysis of the different cellular actors of the tumor microenvironment will be a key step in the implementation of relevant combinations in association with the TA99 mAb. This work is highlighted by a phase I clinical trial (IMC-20D7S) using flanvotumab (human equivalent of mAb TA99) in 27 patients with metastatic melanoma that shows interesting clinical outcome without severe side effects, opening the way for the development of therapeutic combinations associated with this mAb.
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Laetitia They. Renforcement des effets immunomodulateurs d’un anticorps monoclonal anti-tumoral : étude des effets potentialisateurs de thérapies combinées et analyse des mécanismes impliqués. Médecine humaine et pathologie. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT076⟩. ⟨tel-02045505⟩

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