Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis.

UNLABELLED: Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by anti-CD20 monoclonal antibodies. CD19-targeted chimeric antigen receptor (CAR)-T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33×10^8 autologous anti-CD19 CAR-T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50's year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60's year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR-T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles. In the 2 subjects with progressive MS reported here, low dose anti-CD19 CAR-T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR-T cell therapy in MS.

ONE SENTENCE SUMMARY: Anti-CD19 CAR-T cell was safe in two progressive MS patients with CSF penetration, OCB/IgG index resolution, and improved inflammatory background.