(467b) Optimized or-Gate Chimeric Antigen Receptor for Adoptive T-Cell Therapy Against B-Cell Malignancies

Cell-based immunotherapy, or the use of living cells to modulate the immune system and combat diseases, has garnered intensifying interest among researchers and clinicians. In particular, several clinical trials of adoptive T-cell therapy have demonstrated that T cells engineered to express chimeric antigen receptors (CARs) specific for the pan–B-cell marker CD19 can eradicate both acute and chronic B-cell malignancies in patients with relapsing disease. However, CARs tested in clinical trials to-date remain single-input signal processing units that are vulnerable to mutational escape—i.e., tumors can evade T-cell targeting by eliminating the single antigen recognized by the CAR. Indeed, case of relapse has been reported after CD19 CAR-T cell treatment due to the emergence of CD19-negative B-cell leukemia. Here, we report the development and systematic optimization of a next-generation CAR capable of OR-gate signal processing. Specifically, we have constructed CD19-OR-CD20 CARs that trigger T-cell–mediated cell lysis in response to either CD19 or CD20, both markers commonly found on B-cell malignancies. We demonstrate that the optimal CAR architecture is dependent on the targeted antigen and can be systematically optimized through rational design. This represents the first bispecific CAR with clinically relevant antigen inputs for cancer therapy.