靶向cd19和靶向bcma的CAR-T细胞联合输注治疗难治性系统性红斑狼疮:一项1期试验

IF 50 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jingjing Feng, Dawei Huo, Ruimin Hong, Xuexiao Jin, Heng Cao, Mi Shao, Rui Wen, Qiqi Zhang, Mingming Zhang, Shan Fu, Dongrui Wang, Huijun Xu, Guoqing Wei, Jiazhen Cui, Simao Huang, Dawei Cui, Alex Hongsheng Chang, Zhihong Liu, Linrong Lu, Jin Lin, Yongxian Hu, He Huang
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引用次数: 0

摘要

系统性红斑狼疮(SLE)仍然难治性常规免疫抑制患者的亚群。在难治性SLE中,我们发现外周CD19 + B细胞和骨髓CD19 - BCMA +长寿浆细胞是主要的自身抗体来源,激发CD19和BCMA双重靶向。在这里,我们报告了一组患者(14名女性,1名男性)在氟达拉滨/环磷酰胺淋巴细胞清除后共同输注自体抗cd19和抗bcma嵌合抗原受体(CAR) T细胞的1期剂量递增试验的结果。主要终点是28天内的剂量限制性毒性(dlt)和12周内的不良事件;关键次要终点包括在12周内达到狼疮低疾病活动状态(LLDAS)和DORIS缓解,以及在24周内达到体内CAR-T持续。探索性终点是输注后B细胞耗竭的持续时间和恢复时间,免疫重建动力学以及CAR-T治疗后自身抗体滴度和血清免疫球蛋白浓度的纵向变化。在中位712天的随访(613- 1134天)中,未发生dlt。86.7%的患者出现1级细胞因子释放综合征,无神经毒性或治疗相关死亡。最常见的3级或以上不良事件是中性粒细胞减少(100%)、血小板减少(40%)和贫血(13.3%),所有这些不良事件在支持治疗下都是可逆的。到第12周,15例患者中有12例(80%)同时满足LLDAS和DORIS缓解标准。多组学分析证实了自身反应性CD19 + BCMA +克隆的消除、初始IgM/IgD B细胞的重构以及干扰素刺激和bba依赖信号的持续下调,表明免疫稳态得到改善。对3名患者1年的纵向监测显示,致病性克隆持续根除,表明可能治愈。双抗cd19 /抗bcma CAR-T细胞疗法治疗难治性SLE具有良好的安全性和良好的临床疗效。本研究支持进一步发展这种治疗方法用于rle患者。ClinicalTrials.gov标识符:NCT05030779。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Co-infusion of CD19-targeting and BCMA-targeting CAR-T cells for treatment-refractory systemic lupus erythematosus: a phase 1 trial.

Systemic lupus erythematosus (SLE) remains refractory to conventional immunosuppression in a subset of patients. In treatment-refractory SLE, we show that peripheral CD19 B cells and bone marrow CD19⁻BCMA⁺ long-lived plasma cells are dominant autoantibody sources, motivating dual CD19 and BCMA targeting. Here we report results from a cohort of patients (14 female, one male) in an ongoing phase 1 dose-escalation trial of co-infused autologous anti-CD19 and anti-BCMA chimeric antigen receptor (CAR) T cells after fludarabine/cyclophosphamide lymphodepletion. Primary endpoints were dose-limiting toxicities (DLTs) within 28 days and adverse events within 12 weeks; key secondary endpoints comprised attainment of Lupus Low Disease Activity State (LLDAS) and DORIS remission within 12 weeks and in vivo CAR-T persistence within 24 weeks. Exploratory endpoints were the duration of post-infusion B cell depletion and time to recovery, the kinetics of immune reconstitution and longitudinal changes in autoantibody titers and serum immunoglobulin concentrations after CAR-T therapy. Over a median 712-day follow-up (range, 613-1,134), no DLTs occurred. Grade 1 cytokine release syndrome developed in 86.7% of patients, with no neurotoxicity or treatment-related deaths. The most common grade 3 or higher adverse events were neutropenia (100%), thrombocytopenia (40%) and anemia (13.3%), all of which were reversible with supportive care. By week 12, 12 of 15 patients (80%) fulfilled both the LLDAS and DORIS remission criteria. Multiomic analyses confirmed elimination of autoreactive CD19⁺BCMA⁺ clones, reconstitution of naive IgM/IgD B cells and durable downregulation of interferon-stimulated and BAFF-dependent signatures, indicating improved immune homeostasis. Longitudinal monitoring of three patients for 1 year demonstrated sustained eradication of pathogenic clones, suggesting potential cure. Dual anti-CD19/anti-BCMA CAR-T cell therapy demonstrates good safety and promising clinical efficacy in treatment-refractory SLE. This study supports the further development of this treatment approach for patients with rSLE. ClinicalTrials.gov identifier: NCT05030779 .

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来源期刊
Nature Medicine
Nature Medicine 医学-生化与分子生物学
CiteScore
100.90
自引率
0.70%
发文量
525
审稿时长
1 months
期刊介绍: Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.
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