Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8⁺ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

中文翻译：

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中枢神经系统自身免疫患者抗 BCMA CAR T 细胞治疗的单细胞分析

嵌合抗原受体 (CAR) T 细胞免疫疗法治疗神经性自身免疫性疾病前景广阔，但对 CAR T 细胞动力学和治疗后的免疫改变知之甚少。在这里，我们对接受抗 B 细胞成熟抗原 (BCMA) CAR T 细胞治疗的视神经脊髓炎谱系障碍 (NMOSD) 患者的配对脑脊液 (CSF) 和血液样本进行了单细胞多组学测序。增殖细胞毒性样CD8+CAR T 细胞克隆被确定为自身免疫的主要效应器。具有增强趋化性的抗 BCMA CAR T 细胞可有效穿过血液-脑脊液屏障，消除脑脊液中的浆母细胞和浆细胞，并抑制神经炎症。输注产品中表达 CD44 的早期记忆表型可能与 CAR T 细胞在自身免疫中的持续存在相关。此外，与来自血液恶性肿瘤的细胞相比，来自 NMOSD 患者的 CAR T 细胞表现出细胞毒性受到抑制的独特特征。因此，我们提供了有关神经性自身免疫性疾病患者 CAR T 细胞功能的机制见解。