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.