T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity

Chimeric antigen receptor (CAR) T cell therapy lacks persistent efficacy with on-target, off-tumortoxic-ities for treating solid tumors. Thus, an antibody-guided switchable CAR vector, the chimeric Fc receptor CD64 (CFR64), composed of a CD64 extracellular domain, is designed. T cells expressing CFR64 exert more robust cytotoxicity against cancer cells than CFR T cells with high-affinity CD16 variant (CD16v) or CD32A as their extracellular domains. CFR64 T cells also exhibit better long-term cytotoxicity and resis-tance to T cell exhaustion compared with conventional CAR T cells. With trastuzumab, the immunological synapse (IS) established by CFR64 is more stable with lower intensity induction of downstream signaling than anti-HER2 CAR T cells. Moreover, CFR64 T cells exhibit fused mitochondria in response to stimula-tion, while CARH2 T cells contain predominantly punctate mitochondria. These results show that CFR64 T cells may serve as a controllable engineered T cell therapy with prolonged persistence and long-term antitumor activity.

Automated summary

A switchable CAR vector called CFR64, designed with a CD64 extracellular domain, is shown to have better efficacy in treating solid tumors compared to conventional CAR T cells. CFR64 T cells exhibit more robust cytotoxicity, better long-term activity, and resistance to T cell exhaustion. The use of CFR64 with trastuzumab also results in a more stable immunological synapse with lower downstream signaling induction compared to anti-HER2 CAR T cells.