China-New Zealand Joint Laboratory on Biomedicine and Health, State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, the Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Guangzhou Laboratory, Guangzhou, China.
Cell Rep. 2023 Jul 25;42(7):112797. doi: 10.1016/j.celrep.2023.112797. Epub 2023 Jul 11.
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.
嵌合抗原受体 (CAR) T 细胞疗法缺乏持久性疗效，并且在治疗实体瘤时存在“靶向肿瘤，脱靶”毒性。因此，设计了一种抗体引导的可切换 CAR 载体，即嵌合 Fc 受体 CD64（CFR64），由 CD64 细胞外结构域组成。表达 CFR64 的 T 细胞对癌细胞的细胞毒性比具有高亲和力 CD16 变体 (CD16v) 或 CD32A 作为其细胞外结构域的 CFR T 细胞更强。与传统的 CAR T 细胞相比，CFR64 T 细胞还表现出更好的长期细胞毒性和对 T 细胞耗竭的抗性。用曲妥珠单抗，CFR64 建立的免疫突触 (IS) 诱导下游信号的强度较低，但诱导强度比抗 HER2 CAR T 细胞更高。此外，CFR64 T 细胞在受到刺激时表现出融合的线粒体，而 CARH2 T 细胞则主要包含点状线粒体。这些结果表明，CFR64 T 细胞可能作为一种可控的工程 T 细胞疗法，具有延长的持久性和长期抗肿瘤活性。
