CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-06-14 Epub Date: 2024-03-29 DOI:10.1016/j.medj.2024.03.002

Felix Fischbach, Johanna Richter, Lena Kristina Pfeffer, Boris Fehse, Susanna Carolina Berger, Stefanie Reinhardt, Jens Kuhle, Anita Badbaran, Kristin Rathje, Nico Gagelmann, Dominic Borie, Johan Seibel, Francis Ayuk, Manuel A Friese, Christoph Heesen, Nicolaus Kröger

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引用次数: 0

Abstract

Background: Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases.

Methods: Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS.

Findings: CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64.

Conclusions: CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19⁺ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted.

Funding: Both individual treatments as well the generated data were not based on external funding.

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对两名多发性硬化症患者进行 CD19 靶向嵌合抗原受体 T 细胞治疗。

背景：进展性多发性硬化症（MS）的特征是中枢神经系统（CNS）中的免疫细胞（包括 B 细胞）增殖引起的分区性烟雾状神经炎症。虽然在疾病早期可以通过免疫调节疗法预防炎症活动，但此类疗法通常无法阻止疾病的进展。CD19 嵌合抗原受体（CAR）-T 细胞疗法在血液恶性肿瘤领域掀起了一场革命。虽然CAR-T细胞疗法普遍被认为具有疗效，但也观察到与之相关的严重不良事件，如免疫效应细胞相关神经毒性综合征（ICANS）。最近观察到 CD19 CAR-T 细胞成功用于系统性红斑狼疮等风湿性疾病和重症肌无力等神经免疫性疾病，这表明它有可能应用于其他自身免疫性疾病。方法：在此，我们报告了首次使用全人 CD19 CAR-T 细胞疗法（KYV-101）对两名进行性多发性硬化症患者进行的个体治疗：结果：CD19 CAR-T细胞给药对两名患者都具有可接受的安全性。尽管在脑脊液中检测到了 CD19 CAR-T 细胞，但未观察到 ICANS。在病例 1 中，CAR-T 细胞输注后脑脊液中的鞘内抗体生成明显减少，并持续到第 64 天：结论：在进行性多发性硬化症中应用 CD19 CAR-T 细胞具有可接受的安全性。在脑脊液中观察到了 CAR-T 细胞的存在和扩增，但没有出现神经毒性的临床症状，这与鞘内抗体的减少一起，表明 CAR-T 细胞对中枢神经系统 CD19+ 靶细胞的扩增依赖性效应。我们有理由对 CD19 CAR-T 细胞在多发性硬化症中的应用进行更大规模的临床研究：单项治疗和生成的数据均未获得外部资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

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