Cell Reports (Jul 2023)

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

  • 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

Journal volume & issue
Vol. 42, no. 7
p. 112797

Abstract

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Summary: 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.

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