Dr. Chenqi Xu

Clinical success of CAR-T cell therapy in cancer treatment demonstrates the tremendous potential of cell medicine and reveals the arrival of a new era of drug development. However, major clinical challenges including high relapse rate and adverse effect remain to be resolved. Compared with the native antigen receptor TCR, synthetic CAR constructs show poor antigen sensitivity and hardly induce persistent T-cell responses. TCR contains four CD3 signaling chains while CAR only utilizes one of them. CD3e is a multi-functional protein that can regulate TCR signaling, clustering and surface expression. Incorporation of CD3e into CAR constructs promotes long-term killing through amelioration of cell exhaustion and meanwhile reduces cytokine production. These benefits depend on the unique CD3e ITAM that can be mono-phosphorylated to recruit an inhibitory molecule Csk. Enhancing CD3 diversity thus represents a promising direction to improve clinical performance of CAR-T cell therapy.