Altering CAR Construct Design to Ameliorate CAR-T Cell Therapy Associated Cytokine Release Syndrome

Cytokine release syndrome represents a significant barrier to the widespread application of chimeric antigen receptor (CAR)-T cell therapies. We performed a broad analysis of preclinical and clinical studies that tested different designs of the CAR construct to tune CAR signaling, with an emphasis on effects of CAR designs on cytokine release from activated CAR-T cells. Evidence from these studies has shown that CAR signal strength and induced cytokine release can be effectively tuned by choosing different antigenbinding domains, hinge and transmembrane regions, costimulatory domains, and activation domains of a CAR construct. The detailed understanding in this aspect will pave the way to develop CAR-T cell products that exert robust anti-cancer function without the exceeding release of cytokines, thus fulfilling their promise in cancer therapy.