Zola-Cel and Treatment-Free Remission: What the BREAKFREE-2 Data Show

Zolacabtagene autoleucel (zola-cel; Bristol Myers Squibb) is an investigational, autologous CD19-directed CAR T cell therapy being evaluated in multiple sclerosis (MS) in the phase 1 BREAKFREE-2 study. The approach aims to achieve an immune reset through complete B cell depletion, with the goal of durable disease control and potentially treatment-free remission. Interim results were presented at MSToronto 2026, the 10th Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The analysis included 66 patients with highly active relapsing MS (30) or progressive MS (36) who had a median of 2 prior disease-modifying therapies (DMTs). All 60 patients treated at dose level 2 remained off DMTs at last follow-up, including 9 with more than 12 months of follow-up. Cytokine release syndrome occurred in 42.4% of patients, mostly grade 1. After the data cutoff, one patient with highly active relapsing MS died of septic pneumonia.

To help put these findings in context, NeurologyLive® spoke with Jeffrey Cohen, MD, a professor of neurology and staff physician at the Cleveland Clinic Mellen Center for Multiple Sclerosis. He answered questions on the early efficacy signals, how to interpret treatment-free outcomes, the rationale behind immune reset, remaining safety considerations, and which patients may be best suited for CAR T cell therapy.

NeurologyLive: From BREAKFREE-2, what were the most notable efficacy signals, particularly regarding relapse control, disability progression, and disease activity?

Jeffrey Cohen, MD: As a phase 1 study, the primary end point of the BREAKFREE-2 trial was safety and tolerability of zola-cel. Secondary outcomes included assessments of efficacy. All the participants had ongoing disease activity and/or disability worsening at baseline prior to the trial despite treatment with high-efficacy medication. Among 30 participants with haRMS, 7 were evaluable for no evidence of disease activity (NEDA) with follow-up of 26 weeks or more. One participant had a nonenhancing enlarged brain MRI lesion at day 29. Other than that, there were no relapses, active MRIs, or worsening Expanded Disability Status Scale (EDSS) scores. All 8 participants evaluable for EDSS with follow-up of 26 weeks or more had stable or improved EDSS. Among 36 participants with PMS, 24 were evaluable for EDSS change with follow-up of 26 weeks or more. Of those, 22 had stable or improved EDSS, including 3 with 3-month confirmed EDSS improvement. In addition, 92% had stable or improved timed 25-foot walk and 9-hole peg test scores. There were no active MRIs among the 24 PMS participants.

All patients treated at dose level 2 remained off disease-modifying therapies at their last follow-up. How should clinicians interpret these early findings, and what additional evidence is needed to establish the potential for durable, treatment-free remission?

All participants in BREAKFREE-2 remained off DMTs, including 9 with 12 months or more of follow-up. This finding supports the durable efficacy of zola-cel CAR T cell therapy. Experience with more participants and longer follow-up will be necessary to confirm the consistency and duration of treatment-free remission.

What is the rationale behind achieving an immune reset in MS, and how might this translate into more sustained disease control?

An important difference between B-cell-directed CAR T cell therapy and B-cell-depleting monoclonal antibodies is much deeper B-cell depletion, not only of B cells circulating in the blood but also of those within tissues, including the central nervous system (CNS). This deeper depletion might lead to greater efficacy, particularly for the compartmentalized, nonresolving chronic inflammation that is one of the drivers of progression. B-cell repopulation after the deep depletion comprises a more naïve B-cell phenotype with decreased memory B cells, suggesting an immune reset, which might lead to long-lasting efficacy.

What have the BREAKFREE-2 findings revealed about the safety profile of zola-cel, and what risks will require closer evaluation as development progresses?

Although data are rapidly accumulating, overall experience with zola-cel and CAR T cell therapy in MS and other autoimmune diseases remains relatively limited. The grade 5 adverse event, septic pneumonia following cyclophosphamide treatment of severe refractory extrapyramidal symptoms, that occurred in BREAKFREE-2 teaches us that, although safety and efficacy generally have been good, CAR T cell therapy has the potential for rare but significant complications. We are still learning the spectrum of those potential complications, the risk factors, both related to the target populations and the CAR T cell product, and optimal management. CAR T cell therapy appears promising in MS and other autoimmune diseases but remains investigational.

Looking ahead, which patient populations might be best suited for CAR T cell therapy, and what are the most important questions that future studies need to address before this approach could become part of routine MS care?

The emerging results of BREAKFREE-2 and other CAR T cell trials support benefit in both treatment-refractory relapsing MS and PMS. Further experience, more data on efficacy, and more data on safety are needed to determine which MS patient population, or both, is suited to CAR T cell therapy.

For more MSToronto 2026 coverage, click here.