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

Cell reports 2023 Jul 25

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Chimeric antigen receptor (CAR) T cell therapy lacks persistent efficacy with "on-target, off-tumor" toxicities 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 resistance 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 stimulation, 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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Yuanbin Cui, Tingjie Yuan, Ying Wang, Diwei Zheng, Le Qin, Shanglin Li, Zhiwu Jiang, Shouheng Lin, Wenjing Guo, Zhi Wang, Zhaoduan Liang, Yi Li, Yao Yao, Xingguo Liu, Qiannan Tang, Hai-Yan Tu, Xu-Chao Zhang, Zhaoyang Tang, Nathalie Wong, Zhenfeng Zhang, Dajiang Qin, Jean Paul Thiery, Kailin Xu, Peng Li. T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity. Cell reports. 2023 Jul 25;42(7):112797