CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
表达可切换嵌合 Fc 受体 CD64 的 T 淋巴细胞表现出增强的持久性和抗肿瘤活性
英文原题：T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity.
查看英文原题
T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity.
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中文摘要
嵌合抗原受体（CAR）T细胞疗法在治疗实体瘤时缺乏持久疗效，并存在“靶向、非肿瘤”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胞外结构域组成。表达CFR64的T细胞对癌细胞的细胞毒性比以高亲和力CD16变体（CD16v）或CD32A作为其胞外结构域的CFR T细胞更强。与常规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细胞耗竭的抵抗。与曲妥珠单抗联合使用时，CFR64建立的免疫突触（IS）比抗HER2 CAR-T 细胞更稳定，下游信号诱导强度更低。此外，CFR64 T细胞在刺激下表现出融合的线粒体，而CARH2 T细胞主要含有 punctate 线粒体。这些结果表明，CFR64 T细胞可能作为一种可控的工程化T细胞疗法，具有更长的持久性和长期抗肿瘤活性。
展开英文摘要原文
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.
论文信息
- 作者
- Cui Y、Yuan T、Wang Y、Zheng D、Qin L、Li S、Jiang Z、Lin S
- 第一作者单位
- 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.China
- 通讯作者单位
- 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; Department of Surgery of the Faculty of Medicine, the Chinese University of Hong Kong (CUHK), Hong Kong, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China. Electronic address: li_peng@gibh.ac.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports2023 Jul 25
- 原文标识
- PubMed 37436890 · DOI 10.1016/j.celrep.2023.112797