Anti-BCMA/CD19 CAR T cell therapy in patients with refractory generalized myasthenia gravis: a single-arm, phase 1 trial.

Background: 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. Methods: 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 × 106, 3.0 × 106, and 5.0 × 106 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. Findings: 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. Interpretation: 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. Funding: 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.