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B 细胞谱系重建是 CAR-T 细胞治疗难治性重症肌无力患者疗效的基础。

B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis.

机构信息

Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.

Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, 430030, Wuhan, China.

出版信息

EMBO Mol Med. 2024 Apr;16(4):966-987. doi: 10.1038/s44321-024-00043-z. Epub 2024 Feb 26.

Abstract

B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8 Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.

摘要

B 细胞成熟抗原(BCMA)在浆母细胞和浆细胞中表达,可作为自身免疫性疾病的有前途的治疗靶点。我们在此报告了针对两名重症肌无力(一名具有 AChR-IgG,一名具有 MuSk-IgG)高度复发和难治性患者的靶向 BCMA 的嵌合抗原受体(CAR)T 细胞。两名患者均表现出良好的安全性和长达 18 个月的持续临床改善。致病性自身抗体持续减少的 B 细胞谱系重建可能是治疗效果的基础。为了确定 CAR-T 细胞在这些患者中的治疗效果的可能机制,对输注后以及其匹配的输注产品的一系列血液样本进行了纵向单细胞 RNA 和 TCR 测序。通过跟踪 CAR-T 表型的时间演变,我们证明增殖的细胞毒性样 CD8 克隆是自身免疫的主要效应物,而在输注前 CD8 Te 细胞中受损的细胞毒性和增殖特征以及深刻的线粒体功能障碍,以及随后在制造后受损的 CAR-T 细胞,可能解释了它们在这些患者中的特征。我们的发现可能指导未来的研究,以改善自身免疫性疾病的 CAR T 细胞免疫疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e7a/11018773/7bd363888666/44321_2024_43_Fig1_HTML.jpg

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