Zhang Yong, Liu Dan, Zhang Zhouao, Huang Xiaoyu, Cao Jiang, Wang Gang, Li Huizhong, Li Shengli, Zhang Shenyang, Zhang Wei, Chen Hao, Du Xue, Wang Zhouyi, Yang Mingjin, Luo Tiancheng, Guo Xinyan, Ma Tianyu, Peng Deyou, Qi Guoyan, Zong Shenghua, Cui Guiyun, Zheng Junnian, Shi Ming
Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China.
EClinicalMedicine. 2025 Oct 31;90:103621. doi: 10.1016/j.eclinm.2025.103621. eCollection 2025 Dec.
Treating refractory generalized myasthenia gravis is still a big challenge, so new treatments are needed. Several studies have shown the potential of chimeric antigen receptor (CAR) T cell therapy in the treatment of autoimmune diseases. However, no clinical trial of bispecific CAR T cells targeting refractory myasthenia gravis has been done. We developed autologous anti-B-cell maturation antigen (BCMA) and CD19 bispecific CAR T cells to evaluate the safety and efficacy in refractory myasthenia gravis.
This single-arm, phase 1 trial (ChiCTR2200061267) was conducted at the Affiliated Hospital of Xuzhou Medical University in refractory generalized myasthenia gravis patients (Myasthenia Gravis Activities of Daily Living [MG-ADL] ≥6-point, and Quantitative Myasthenia Gravis scale [QMG] ≥8-point). Anti-BCMA/CD19 bispecific CAR T cells were administered at 1.0 × 10, 3.0 × 10, and 5.0 × 10 CAR T cells per kg. Primary endpoints assessed safety (dose-limiting toxicities, maximum tolerated dose, and adverse events); secondary endpoints assessed disease severity and other related indexes.
Between May 3, 2023, and June 19, 2024, 18 patients were enrolled and received apheresis and a single CAR T cell infusion. Mean age was 41 years (SD 12) and 12 (67%) participants were female. The anti-BCMA/CD19 bispecific CAR T cells were generally safe, with no dose-limiting toxicities, no immune effector cell-associated neurotoxicity syndrome, and only grade 1 cytokine release syndrome (39% of patients). The most common grade 3 or worse adverse events within 28 days were hematological toxicities, including three leukopenia, three neutropenia, one anaemia, and one thrombocytopenia. All were transient and manageable. 17 participants completed follow-up. Clinical improvements by day 180 were -8.6 (95% CI -10.2 to -7.0) for MG-ADL score and -15.4 (-17.6 to -13.2) for QMG score. 14 participants (82%) achieved minimal manifestations, 15 (88%) stopped glucocorticoids, all stopped non-steroidal immunosuppressants, and eight (47%) had anti-acetylcholine receptor antibody negative seroconversion.
Anti-BCMA/CD19 CAR T cells showed good safety and efficacy in refractory generalized myasthenia gravis. A large proportion of participants had a minimal manifestation status and discontinued glucocorticoids and non-steroidal immunosuppressants, and a certain proportion of anti-acetylcholine receptor antibodies turned negative.
National Natural Science Foundation of China, Basic Research Program of Jiangsu, Young academic leaders of Jiangsu Qinglan Project, and Construction Project of High Level Hospital of Jiangsu Province.
治疗难治性全身型重症肌无力仍然是一项巨大挑战，因此需要新的治疗方法。多项研究显示了嵌合抗原受体（CAR）T细胞疗法在治疗自身免疫性疾病方面的潜力。然而，尚未开展针对难治性重症肌无力的双特异性CAR T细胞的临床试验。我们研发了自体抗B细胞成熟抗原（BCMA）和CD19双特异性CAR T细胞，以评估其在难治性重症肌无力中的安全性和疗效。
这项单臂1期试验（ChiCTR2200061267）在徐州医科大学附属医院对难治性全身型重症肌无力患者（重症肌无力日常生活活动能力[MG-ADL]≥6分，重症肌无力定量评分[QMG]≥8分）开展。以每千克1.0×10、3.0×10和5.0×10个CAR T细胞的剂量给予抗BCMA/CD19双特异性CAR T细胞。主要终点评估安全性（剂量限制性毒性、最大耐受剂量和不良事件）；次要终点评估疾病严重程度和其他相关指标。
在2023年5月3日至2024年6月19日期间，18例患者入组并接受了血细胞分离术和单次CAR T细胞输注。平均年龄为41岁（标准差12），12例（67%）参与者为女性。抗BCMA/CD19双特异性CAR T细胞总体安全，未出现剂量限制性毒性，未出现免疫效应细胞相关神经毒性综合征，仅1级细胞因子释放综合征（39%的患者）。28天内最常见的3级或更严重不良事件为血液学毒性，包括3例白细胞减少、3例中性粒细胞减少、1例贫血和1例血小板减少。所有均为短暂性且可控制。17例参与者完成随访。至第180天时，MG-ADL评分的临床改善为-8.6（95%CI -10.2至-7.0），QMG评分为-15.4（-17.6至-13.2）。14例参与者（82%）达到最小表现状态，15例（88%）停用糖皮质激素，全部停用非甾体类免疫抑制剂，8例（47%）出现抗乙酰胆碱受体抗体血清学转阴。
抗BCMA/CD19 CAR T细胞在难治性全身型重症肌无力中显示出良好的安全性和疗效。很大一部分参与者达到最小表现状态并停用了糖皮质激素和非甾体类免疫抑制剂，且一定比例的抗乙酰胆碱受体抗体转阴。
中国国家自然科学基金、江苏省基础研究计划、江苏省青蓝工程青年学术带头人、江苏省高水平医院建设项目。
