Wang Min, DeStefano Vincent M, Ding Ling, Hong Ming, Zeng Ronghao, Wada Masayuki, Pinz Kevin, Chow Jennifer E, Hershkowitz Nicole, Wang Mingxia, Zou Chanjuan, Ma Yu, He Shanzhi, Ma Yupo, Wang Weijia
Department of Rheumatoid Immunology, Zhongshan People's Hospital, Zhongshan, People's Republic of China.
Research & Development Division, iCell Gene Therapeutics Inc., Long Island High Technology Incubator, 25 Health Sciences Drive, Stony Brook, 11790, NY, USA.
Stem Cell Rev Rep. 2025 Jun 23. doi: 10.1007/s12015-025-10923-7.
Autoimmune disorders(AIDs) such as systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), immune thrombocytopenic purpura (ITP), and ANCA-associated vasculitis (AAV) are driven by pathogenic autoantibodies from memory B-cells, plasma cells (PCs) and long-lived plasma cells (LLPCs). Since B-cell-only therapies do not eliminate autoantibodies from PCs/LLPCs, we evaluated our novel BCMA-CD19 compound chimeric antigen receptor T-cell (cCAR) therapy. Building on robust preclinical findings, this study aimed to translate cCAR from bench to bedside for refractory SLE overlap syndrome(OS).
In vitro co-culture assays were performed using BCMA + MM.1S, BCMA + RPMI-8226, and CD19 + K562 cells at various effector to targe ratios. cCAR induced 86-95% lysis of BCMA + targets and 98% lysis of CD19 + cells. In vivo, NSG mice engrafted with BCMA + MM.1S or REH cells received cCAR T-cells, achieving > 99% target clearance by day 15 and a significant survival benefit. Clinically, a 53-year-old woman with a 10-year history of refractory SLE OS and Class III lupus nephritis was preconditioned with cyclophosphamide and infused with 3 × 10⁶ cCAR cells/kg.
Preclinical studies confirmed potent in vitro and in vivo cytotoxicity. Clinically, B-cells became undetectable by day 3 post-infusion, and the patient experienced a transient, manageable grade 1 cytokine release syndrome(CRS). Autoantibodies, complement, and urinary protein normalized; the SLE Disease Activity Index 2000(SLEDAI-2K) score dropped from 8 to 0, with durable, medication-free complete remission maintained for over 1.5 years.
cCAR therapy effectively eliminates pathogenic cell populations, representing a promising translational strategy for treating refractory SLE and related AIDs.
自身免疫性疾病（AIDs），如系统性红斑狼疮（SLE）、干燥综合征（SS）、免疫性血小板减少性紫癜（ITP）和抗中性粒细胞胞浆抗体相关性血管炎（AAV），是由记忆B细胞、浆细胞（PCs）和长寿浆细胞（LLPCs）产生的致病性自身抗体驱动的。由于仅针对B细胞的疗法无法消除PCs/LLPCs中的自身抗体，我们评估了我们新型的BCMA-CD19复合嵌合抗原受体T细胞（cCAR）疗法。基于强有力的临床前研究结果，本研究旨在将cCAR从实验室转化至临床，用于治疗难治性SLE重叠综合征（OS）。
使用BCMA + MM.1S、BCMA + RPMI-8226和CD19 + K562细胞，以不同的效应细胞与靶细胞比例进行体外共培养试验。cCAR诱导BCMA + 靶细胞86%-95%的裂解以及CD19 + 细胞98%的裂解。在体内，移植了BCMA + MM.1S或REH细胞的NSG小鼠接受了cCAR T细胞，到第15天时实现了>99%的靶细胞清除，并具有显著的生存获益。临床上，一名有10年难治性SLE OS病史且患有III级狼疮性肾炎的53岁女性，先接受了环磷酰胺预处理，然后输注了3×10⁶个cCAR细胞/kg。
临床前研究证实了强大的体外和体内细胞毒性。临床上，输注后第3天B细胞检测不到，患者经历了短暂的、可控制的1级细胞因子释放综合征（CRS）。自身抗体、补体和尿蛋白恢复正常；SLE疾病活动指数2000（SLEDAI-2K）评分从8降至0，无药物治疗的持续完全缓解维持了超过1.5年。
cCAR疗法有效消除了致病性细胞群体，是治疗难治性SLE及相关AIDs的一种有前景的转化策略。
