CAR-T Agent Zola-cel Shows No New Multiple Sclerosis Disease Activity in Phase 1 Study

In updated results from the phase 1 Breakfree-2 study (NCT06220201), treatment with zolacabtagene autoleucel (zola-cel; Bristol Myers Squibb), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, showed no new disease activity in patients with highly active relapsing multiple sclerosis (haRMS) and stabilized disability in most patients with progressive MS (PMS). Investigators reported a manageable safety profile after a single infusion, with all cases of cytokine release syndrome (CRS) graded 1 or 2.¹

Presented at the 10th joint ACTRIMS-ECTRIMS meeting (MSToronto), held October 21-23, in Toronto, Canada, results showed that at week 26, all 4 participants with highly active relapsing MS (haRMS) treated at dose level 2 (DL2; 10 × 10⁶ CAR-positive T cells), the expansion-phase dose, achieved no evidence of disease activity (NEDA-3). Among 6 participants with progressive MS (PMS) treated at DL2, 5 (83%) had no 3-month confirmed disability progression (CDP-3). Of these 5 participants, 1 experienced 3-month confirmed disability improvement (CDI-3), and 4 remained stable. The remaining participant experienced CDP-3.¹

Led by Jeffrey A. Cohen, MD, director of the Experimental Therapeutics Program at the Mellen Center for Multiple Sclerosis Treatment and Research at Cleveland Clinic, the study found no new or enlarging T2 lesions or new gadolinium-enhancing lesions after day 29. All participants treated at dose level 2 (DL2) remained off disease-modifying therapy (DMT) at last follow-up. Efficacy analyses were limited to participants with at least 6 months of follow-up.

Evidence of B-Cell Depletion in the CNS and Safety Profile

All participants demonstrated robust zola-cel expansion and complete peripheral B-cell depletion. At week 12, 7 of 10 participants (70%) with detectable oligoclonal bands (OCBs) at baseline showed a reduction in OCBs, which investigators noted indicate B-cell depletion within the central nervous system (CNS).¹

Most grade 3 or higher treatment-emergent adverse events (AEs) across the 57 treated participants were transient cytopenias. CRS occurred in 12 of 21 participants with haRMS (57%; DL1, n = 2; DL2, n = 10) and 12 of 36 with PMS (33%; DL1, n = 1; DL2, n = 11), and all CRS events were grade 1 or 2.¹

Grade 1 or 2 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 1 participant with haRMS and 2 with PMS, all at DL2. One grade 4 ICANS event, in a DL2 participant with PMS, resolved quickly without sequelae.

Study Design and Patient Population

By design, the phase 1, single-arm, dose-escalation Breakfree-2 trial included participants with haRMS or PMS who received a single infusion of zola-cel at 5 × 10⁶ CAR-positive T cells (DL1) or 10 × 10⁶ CAR-positive T cells (DL2) following lymphodepletion. Safety was the primary end point, while preliminary efficacy was assessed in participants with at least 6 months of follow-up using NEDA-3 criteria for haRMS, confirmed disability progression or improvement for PMS, and MRI measures.¹

The study treated 57 total participants, including 21 with haRMS (DL1, n = 3; DL2, n = 18) and 36 with PMS (DL1, n = 3; DL2, n = 33). The PMS cohort included participants with nonrelapsing secondary progressive MS or primary progressive MS (PPMS). Most participants with haRMS had received prior anti-CD20 therapy, and all had experienced disease activity while receiving high-efficacy DMTs.

All participants with PPMS had experienced clinical progression despite ocrelizumab treatment. Median baseline Expanded Disability Status Scale scores were 4.0 (range, 3.0-5.5) in haRMS and 6.0 (range, 4.0-6.0) in PMS, indicating greater baseline disability in the progressive cohort.¹

Zola-cel is manufactured using a next-generation process known as NEX-T. In a separate pooled analysis of 83 participants across the Breakfree-1 and Breakfree-2 studies, presented at the 2026 Tandem Meetings of the American Society for Transplantation and Cellular Therapy and the Center for International Blood and Marrow Transplant Research, cytokine release syndrome (CRS) occurred in 57.8% of participants, ICANS occurred in 12.0%, and 92.8% remained off disease-directed treatment at last follow-up.²

REFERENCES
1. Cohen J, Pul R, Obeidat A, et al. A Phase II, Open-Label, Single-Arm Trial to Evaluate Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Fenebrutinib in Children and Adolescents With Relapsing Multiple Sclerosis (FENerations1): Study Design and Baseline Characteristics. Presented at: The 10 Joint ACTRIMS-ECTRIMS Meeting (MSToronto); October 21-23, 2026; Toronto, Canada.
2. Reshef R, Azzi J, Ayala E, et al. Clinical outcomes from the pooled safety analysis of CD19 NEX-T (BMS-986353), a chimeric antigen receptor (CAR) T cell therapy manufactured using a next-generation process, in severe refractory autoimmune diseases: results from phase 1 Breakfree studies. Presented at: 2026 Tandem Meetings of ASTCT and CIBMTR; February 6, 2026; Salt Lake City, UT.