Characterization of the effect of T cell killing ability and resistance to environmental ROS on the efficiency of CAR-T cell Immunotherapy

Chimeric Antigens Receptor (CAR) T cells adoptive transfer represents a revolutionary strategy in cancer treatment. Indeed, anti-CD19 CAR T cells therapy has dramatically changed the fate of patients with relapsed/refractory (r/r)diffuse large B-cell lymphoma (DLBCL) and related aggressive lymphomas with a reported 52-82% immediate responses. However, only 40% of the patients with these hematologic malignancies achieve complete tumor eradication and prolonged remission and sadly the effectiveness of CAR-T cell therapy against solid tumors is even lower. Indeed, although anti-IL13Rα2-specific CAR- T cells represent a safe approach to treat (GBM), multiple clinical trials have demonstrated that CAR-T cells monotherapy are not highly effective against these solid tumors. Importantly, the escape mechanisms to this immunotherapy are driven by tumor cell complex structural variant resulting from previous line of conventional treatments, alteration of mRNA-editing pathway, oxidative genomic alteration, loss of tumor suppressor and only for asmall fraction the loss of the CD19 antigen in the case of lymphoma. The immunosuppressive tumor microenvironment, the blood brain barrier and tumor heterogeneity account for the inefficiency of CAR-T cell therapy against GBM. It is, therefore, highly likely that the capacity of cancer cell to resist cell death favor the emergence of these variants. Moreover, cytotoxic lymphocytes kill their target in an apoptosis-dependent manner meaning in a non-immunogenic cell death manner. Interestingly, in our laboratory we have found that microenvironmental reactive oxygen species (ROS) strongly impact on the cytotoxic lymphocyte ability to kill the cancer target cells. Suggesting that modulating the cytotoxic lymphocyte sensitivity to environmental ROS could be an innovative strategy to improve CAR-T cell therapy. Therefore, the goal of my project is to characterize the effect of T cell killing ability and resistance to environmental ROS on the efficiency of CAR-T cell Immunotherapy. To achieve this goal, I will develop new generation of CAR-T cell with enhance killing capacity and resistance to environmental ROS to improve CAR-T cell adoptive immunotherapy.