CELL INTELLIGENCE · 肿瘤细胞治疗研究

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CD4(+) T 细胞介导 BCMA CAR-T 细胞治疗后的 CAR-T 细胞相关免疫相关不良事件

英文原题：CD4(+) T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy.

查看英文原题

CD4(+) T cells mediate CAR-T cell-associated immune-related adverse events after BCMA CAR-T cell therapy.

PubMed 2026/01/15（内容时间） Nat Med Q1 · IF 52.5（JCR 2025）

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靶点：BCMA技术：CAR-T多发性骨髓瘤地区：美国
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中文摘要

靶向B细胞成熟抗原（BCMA）的嵌合抗原受体（CAR）T细胞疗法革新了多发性骨髓瘤治疗，但可引起独特毒性，包括颅神经麻痹、帕金森综合征和肠炎，我们将其统称为CAR-T 治疗相关免疫不良事件（CirAE）。在2021年6月至2024年12月期间接受ciltacabtagene autoleucel或idecabtagene vicleucel治疗的198例患者中，27例（13.6%）发生CirAE。其中有一例特别显著：患者发生3种不同CirAE，并伴有CD4⁺ CAR-T 细胞极度扩增（淋巴细胞峰值：197×10³/μL），且该现象在体外可被CCR5抑制所阻断。CirAE与非复发死亡显著增加相关（风险比=5.2，P=0.006）；独立危险因素包括ciltacabtagene autoleucel治疗（比值比=4.5，P=0.058）、输注后前14天峰值绝对淋巴细胞计数≥2.4×10³/μL（比值比=4.3，P<0.001）以及白细胞单采时CD4:CD8比值>1（比值比=2.6，P=0.048）。在所有可获取的CirAE组织中均发现显著CD4⁺ CAR-T 细胞浸润，神经系统CirAE期间的脑脊液中也有此现象，提示CD4⁺ CAR-T 细胞疗法是这些毒性的关键介导因素。

展开英文摘要原文

B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of multiple myeloma but can cause unique toxicities, including cranial nerve palsy, parkinsonism and enterocolitis, which we refer to collectively as CAR T cell therapy-associated immune-related adverse events (CirAEs). Among 198 patients treated with ciltacabtagene autoleucel or idecabtagene vicleucel (June 2021-December 2024), 27 (13. 6%) developed CirAEs.

This included one remarkable case with three distinct CirAEs in association with an extreme CD4 + CAR T cell expansion (peak lymphocytes: 197 10 3 per microliter), which was abrogated in vitro by CCR5 inhibition. CirAEs were associated with significantly higher non-relapse mortality (hazard ratio = 5.

2, P = 0. 006), and independent risk factors included ciltacabtagene autoleucel (odds ratio = 4. 5, P = 0. 058), peak absolute lymphocyte count 2. 4 10 3 per microliter in the first 14 days post-infusion (odds ratio = 4. 3, P < 0. 001) and apheresis CD4:CD8 ratio > 1 (odds ratio = 2. 6, P = 0. 048).

We identified marked CD4 + CAR T cell infiltration in all available CirAE tissues, including cerebrospinal fluid during neurologic CirAEs, implicating CD4 + CAR T cell therapy as a key mediator of these toxicities.

论文信息

作者
Ho M、Paruzzo L、Noll JH、Stella F、Devi P、Ndeupen S、Day YA、Chen GM
第一作者单位
Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.United States
通讯作者单位
Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. jfrai@upenn.edu.United States
期刊
Nature medicine2026 Feb
原文标识
PubMed 41540109　·　DOI 10.1038/s41591-025-04121-8

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