Novel Breakthroughs In CAR T Cell Therapy Against Solid Tumor

Chimeric antigen receptor (CAR) T cell therapy has emerged in the last years as one of the most promising strategies in tumor treatments, in particular against hematological malignancies. This approach consists in devising a synthetic receptor to engineer in most cases T lymphocytes, allowing them to recognize and kill cells expressing a specific antigen in a Major Histocompatibility Complex (MHC) independent manner, therefore leading to a more potent activation. To create a CAR T cell, T lymphocytes are collected from different sources, engineered with the chosen construct, and cultivated in vitro. Afterwards, they are reinfused in the patient in order to exert their cytotoxic activity. Nevertheless, limitations are still an important concern related to CAR T therapy application, especially in solid tumors. These hurdles include antigen escape mechanisms exploited by tumoral cells, on-target off-tumor effects, and the reduced CAR T tumor infiltration. Furthermore, the immunosuppressive microenvironment plays an important role, often altering CAR T cells’ features. To overcome such challenges, various approaches have been employed and assessed. This thesis will concentrate on three studies, each of them focusing on a different strategy to reach better CAR T cells performance in a solid tumor context. The first study focuses on CAR T cells lacking TGF-βR2 to avoid the reported negative impact of TGF-β1 on the anti-tumor response. The second reported study highlights the efficacy of vaccination with amph-ligands in combination with CAR T cells to improve therapy outcomes. Finally, in the third one, a particular CAR cell producing both IL-7 and CCL19 was developed to achieve better results compared to the conventional CAR T cells therapy.