越来越多的证据表明，持续的细胞扩增是嵌合抗原受体 (CAR) T 细胞疗法疗效和毒性的主要驱动因素。在此，我们描述了一个与晚期 CAR T 细胞再扩增相关的延迟性复发性神经毒性的病例。一名 44 岁的患有套细胞淋巴瘤的男性接受了 brexu-cel。输注后，他出现了2级细胞因子释放综合征。第 11 天，报告出现 3 级神经毒性，开始使用大剂量甲基强的松龙，神经系统表现完全缓解。第 30 天，他出现了与 CAR T 细胞重新扩增相关的迟发性 CAR T 细胞毒性。该患者接受托珠单抗和地塞米松治疗，症状得到缓解。第 58 天，他因新发神经毒性再次入院。值得注意的是，观察到新的 CAR T 细胞扩增，脑脊液/血液比率意外升高。该患者立即接受地塞米松治疗，然后升级至大剂量甲泼尼龙和阿那白滞素，其神经系统疾病得到缓解。CAR T 细胞相关的神经毒性通常有一个早期单相过程。据我们所知，这是首例迟发性、复发性神经毒性病例。此外，观察到脑脊液 CAR T 细胞水平升高，这可能表明迟发性神经毒性主要是由 CAR T 细胞的大脑浸润引起的，而不是由细胞因子介导的神经炎症驱动。版权所有 © 2024 国际细胞学会

Mounting evidence suggests that persistent cell expansion is the main driver for both efficacy and toxicity of chimeric antigen receptor (CAR) T-cell therapy. Hereby, we describe a case of delayed recurrent neurotoxicity associated with late CAR T-cells re-expansion.A 44-year-old man suffering from mantle cell lymphoma received brexu-cel. After infusion, he developed grade 2 cytokine release syndrome. On day +11, grade 3 neurotoxicity was reported and high-dose methylprednisolone was started with a complete resolution of neurological manifestations. On day +30, he experienced a late-onset CAR T-cell toxicity associated with CAR T-cell re-expansion. The patient was treated with tocilizumab and dexamethasone, with resolution of symptoms. On day +58, he was readmitted for new onset of neurotoxicity. Notably, a new CAR T-cell expansion was observed, with an unexpectedly elevated cerebrospinal fluid/blood ratio. The patient was promptly treated with dexamethasone and then escalated to high-dose methylprednisolone and anakinra, with resolution of his neurologic condition noted.CAR T-cell-related neurotoxicity usually has an early monophasic course. To our knowledge, this is the first case of late-onset, recurrent neurotoxicity. Moreover, an elevated level of cerebrospinal fluid CAR T cells was observed, which may suggest that the delayed neurotoxicity was primarily caused by the brain infiltration of CAR T cells rather than driven by cytokine-mediated neuroinflammation.Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.