New strategies to improve the efficiency and safety of CAR-T cells for the treatment of B cell lymphoma

Chimeric antigen receptor (CAR) T cells remain one of the most advanced and promising forms of adoptive T-cell immunotherapy. However, the majority of patients with refractory B cell malignancies relapse after CAR T-cell treatment. Our preliminary data show that relapse upon CD19-specific CAR T cell therapy in patients with DLBCL is associated with increased expression of the immune checkpoint ligand CD80 on refractory DLBCL cells potentially leading to inhibition of CAR T cells function by CTLA-4 engagement. To disable this and other immune checkpoint-dependent negative mechanisms of T cell regulation, we have developed a new strategy based on the co-expression of chimeric checkpoint receptors (CCR) on CAR T cells. We will evaluate efficacy and persistence of CAR/CCR T cells in autochthonous mouse models and autologous humanized PDX mouse model of aggressive lymphoma.