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

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单位： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China [2]Hubei Key Laboratory of NeuralInjury and Functional Reconstruction, Huazhong University of Science and Technology, 430030 Wuhan, China [3]Department of Neurology with Institute of TranslationalNeurology, University Hospital Münster, Münster, Germany [4]Nanjing IASO Biotechnology Co.,Ltd, 210018 Nanjing, China [5]Department of Hematology, Tongji Hospital of TongjiMedical College, Huazhong University of Science and Technology, 430030 Wuhan, China

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关键词： Chimeric Antigen Receptor (CAR) T-cell Immunotherapy Refractory Myasthenia Gravis B Cell Maturation Antigen Single-Cell RNA Sequencing

摘要：

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.© 2024. The Author(s).

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出版当年[2023]版：

大类 | 1 区

医学

小类 | 1 区医学：研究与实验

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区医学：研究与实验

第一作者：

第一作者单位： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China [2]Hubei Key Laboratory of NeuralInjury and Functional Reconstruction, Huazhong University of Science and Technology, 430030 Wuhan, China

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通讯机构： [1]Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China [2]Hubei Key Laboratory of NeuralInjury and Functional Reconstruction, Huazhong University of Science and Technology, 430030 Wuhan, China

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