Single-cell profiling of immune reset in patients with refractory generalized myasthenia gravis receiving autologous CD19/BCMA CAR-T cell therapy.

BACKGROUND Chimeric antigen receptor (CAR) T cells targeting CD19 or B cell maturation antigen (BCMA) hold great promise to treat neuroimmune disorders, but the efficacy of CD19/BCMA dual-targeting CAR-T cells and their impact on systemic immunity are poorly understood.

METHODS In this phase 1 study (ClinicalTrials.gov: NCT06371040), patients with refractory generalized myasthenia gravis (gMG) received autologous CD19/BCMA CAR-T cells without prior lymphodepletion. The primary endpoint was the frequency and severity of treatment-emergent adverse events at week 4. Secondary endpoints included changes in MG-specific scale scores. Single-cell RNA sequencing and flow cytometry were performed to characterize longitudinal changes in B cell, plasma cell, and T cell compartments following CAR-T cell infusion.

FINDINGS CD19/BCMA CAR-T cells expanded in vivo, leading to depletion of B cells and plasma cells. All six patients had a favorable safety profile. Minimal symptom expression (MG Activities of Daily Living Score [MG-ADL] = 0) was achieved in five patients by day 90, with responses sustained through day 120-150, and all patients discontinued glucocorticoids while reducing immunosuppressant use. Immune profiling revealed a transient decline in memory B cells and plasma cells. The repopulated B cells exhibited attenuated B cell receptor signaling and increased inhibitory signals derived from bone marrow niche cells. Further, clonal expansion of T and B cells was significantly reduced.

CONCLUSIONS CD19/BCMA CAR-T cell therapy is safe and effective in refractory gMG without lymphodepletion, leading to systemic immune reset that warrants future investigations in larger clinical trials.

FUNDING This study was supported by the National Key Research and Development Program and the National Natural Science Foundation of China.