Feng Jingjing, Huo Dawei, Hong Ruimin, Jin Xuexiao, Cao Heng, Shao Mi, Wen Rui, Zhang Qiqi, Zhang Mingming, Fu Shan, Wang Dongrui, Xu Huijun, Wei Guoqing, Cui Jiazhen, Huang Simao, Cui Dawei, Chang Alex Hongsheng, Liu Zhihong, Lu Linrong, Lin Jin, Hu Yongxian, Huang He
Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Nat Med. 2025 Nov;31(11):3725-3736. doi: 10.1038/s41591-025-03937-8. Epub 2025 Sep 24.
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 .
系统性红斑狼疮（SLE）在一部分患者中对传统免疫抑制治疗仍具有难治性。在治疗难治性SLE中，我们发现外周血CD19 B细胞和骨髓CD19⁻BCMA⁺长寿浆细胞是主要的自身抗体来源，这促使人们对CD19和BCMA进行双重靶向治疗。在此，我们报告了一组患者（14名女性，1名男性）在一项正在进行的1期剂量递增试验中的结果，该试验在氟达拉滨/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。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）和多系统受累系统性红斑狼疮缓解（DORIS缓解）以及在24周内体内CAR-T细胞的持久性。探索性终点是输注后B细胞耗竭的持续时间和恢复时间、免疫重建的动力学以及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天的随访期（范围613 - 1134天）内，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级或更高等级不良事件是中性粒细胞减少（100%）、血小板减少（40%）和贫血（13.3%），所有这些在支持治疗下均可逆转。到第12周时，15名患者中有12名（80%）达到了LLDAS和DORIS缓解标准。多组学分析证实自身反应性CD19⁺BCMA⁺克隆被清除、幼稚IgM/IgD B细胞重建以及干扰素刺激和BAFF依赖性特征的持久下调，表明免疫内环境稳定得到改善。对三名患者进行的为期1年的纵向监测显示致病性克隆持续被清除，提示可能治愈。双重抗CD19/抗BCMA CAR-T细胞疗法在治疗难治性SLE中显示出良好的安全性和有前景的临床疗效。本研究支持对难治性SLE患者进一步开发这种治疗方法。临床试验注册号：NCT05030779 。
