Bristol Myers Squibb Reports Early Safety and Efficacy Results for Investigational CAR T-Cell Therapy Zola-Cel in Multiple Sclerosis
Bristol Myers Squibb has announced interim safety and efficacy findings from the multiple sclerosis (MS) cohorts of the Phase 1 Breakfree-2 clinical study evaluating zolacabtagene autoleucel (zola-cel; BMS-986353), an investigational autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy. The study is assessing the potential of the treatment in patients with highly active relapsing multiple sclerosis (haRMS) and progressive forms of multiple sclerosis (PMS), including individuals who continue to experience disease activity or worsening disability despite treatment.
The findings are being presented in an oral presentation, Abstract #1615, at MSToronto 2026, the 10th Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), taking place in Toronto, Canada.
The interim results provide early evidence of the investigational therapy’s safety profile and potential clinical activity across both relapsing and progressive forms of MS. The findings also highlight the possibility of reducing patients’ reliance on long-term disease-modifying therapies (DMTs), although additional research and longer follow-up will be needed to establish the durability and clinical significance of these outcomes.
Breakfree-2 is a Phase 1, single-arm, dose-escalation study designed primarily to evaluate the safety of zola-cel. Efficacy measures are included as secondary endpoints. According to Bristol Myers Squibb, the results are generally consistent with previously reported Phase 1 data for the therapy and demonstrate early signs of disease control in the patients evaluated.
Breakfree-2 study evaluates 66 patients with multiple sclerosis
The study included 66 patients, comprising 30 individuals with highly active relapsing MS and 36 with progressive forms of the disease. Participants had experienced ongoing disease activity or worsening disability despite receiving previous treatment.
Patients had received a median of two prior disease-modifying therapies. The number of previous therapies ranged from one to eight among patients with haRMS and from one to six among those with PMS. This treatment history reflects a population in which existing therapies had not adequately controlled disease activity or prevented further disability in all patients.
Zola-cel is an investigational autologous CAR T-cell therapy directed against CD19, a protein expressed on B cells. B cells are involved in several immune processes that contribute to multiple sclerosis, including the activation and maintenance of abnormal immune responses. By targeting CD19-positive B cells, CAR T-cell therapy is being investigated as a way to produce a deeper immune reset than may be achieved with conventional disease-modifying treatments.
The autologous approach uses a patient’s own T cells, which are modified to recognize the intended target before being administered back to the patient. In the context of autoimmune disease, the goal is to eliminate disease-associated immune cells and potentially allow the immune system to reconstitute in a way that reduces harmful autoimmune activity.
Unlike many established MS treatments that require ongoing administration, the investigational approach is being studied for its potential to provide sustained disease control following a single treatment course. However, the long-term durability of this effect and the extent to which it could reduce or eliminate the need for further treatment remain under investigation.
The primary endpoint of Breakfree-2 is safety, while efficacy is assessed through secondary measures, including disease activity, disability progression and magnetic resonance imaging (MRI) findings.
Safety results show mostly brief and reversible adverse events
According to Bristol Myers Squibb, the majority of adverse events reported in the study were brief and reversible, broadly consistent with previously reported Phase 1 clinical data for zola-cel. Nevertheless, the interim findings included clinically significant events that highlight the need for careful safety monitoring as the therapy continues through development.
Cytokine release syndrome (CRS) was reported in 28 of the 66 patients, representing 42.4% of the study population. Most cases were Grade 1, occurring in 36.4% of all patients, while Grade 2 CRS occurred in 6.1%. All reported CRS events resolved, with a median resolution time of two days.
CRS is an inflammatory response that can occur after CAR T-cell therapy as activated immune cells release cytokines. Its severity can vary, making early recognition and appropriate management important components of treatment delivery.
Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in five patients, or 7.6% of the study population. Most cases were Grade 1 or Grade 2, and the events resolved within a median of two days.
One Grade 4 ICANS event was reported in a patient with progressive MS. The event was managed with corticosteroids and anakinra and resolved within four days. Although this event resolved, its severity underscores the importance of monitoring neurological symptoms closely in patients receiving investigational CAR T-cell therapy, particularly because neurological manifestations may be challenging to distinguish from symptoms associated with the underlying disease.
The company also disclosed a fatal event that occurred after the data cutoff. A patient with highly active relapsing MS experienced septic pneumonia and died 44 days after receiving zola-cel.
Following infusion, the patient developed late-onset motor symptoms that were not classified as ICANS. These symptoms did not resolve with intermittent corticosteroids and intravenous immunoglobulin (IVIG). Although the patient’s CAR T-cell expansion was consistent with the pattern observed across the study, high-dose cyclophosphamide was administered. The patient subsequently developed septic pneumonia and died the following day.
The reported circumstances highlight the complexity of managing serious complications following immune-modulating cellular therapies. The available information does not establish that zola-cel directly caused the fatal event, and the specific clinical circumstances require careful assessment as part of the ongoing safety evaluation.
Bristol Myers Squibb stated that no additional Grade 5 events had been reported across its autoimmune disease CAR T-cell development programs, which included 190 patients treated in Phase 1 studies. The fatal event remains an important consideration in evaluating the overall benefit-risk profile of the investigational treatment.
As the study progresses, additional data will be needed to characterize the incidence, timing and severity of adverse events, as well as the potential for delayed complications. The safety profile will remain a central consideration as investigators assess whether the possible benefits of a treatment designed to reset the immune system outweigh its risks.
All patients treated at dose level 2 remained off disease-modifying therapies
The efficacy findings provide early evidence of the potential for zola-cel to produce sustained immune effects in patients with relapsing and progressive MS.
At the latest follow-up, all 60 patients treated at dose level 2 (DL2) remained off disease-modifying therapies. This included nine patients who had more than 12 months of follow-up.
The observation is notable because disease-modifying therapies are commonly used to reduce inflammatory disease activity and limit the risk of relapses or disability accumulation in multiple sclerosis. The possibility of maintaining disease control without ongoing DMT use could represent an important treatment objective for patients who continue to experience disease activity despite previous therapies.
The company attributed the findings to the potential for immune reset through complete B-cell depletion. However, remaining off DMTs alone does not establish treatment-free remission or prove that disease activity will remain controlled over the long term. Longer follow-up will be needed to determine whether patients can maintain these outcomes without additional treatment and whether the effects differ between relapsing and progressive forms of MS.
The results also require interpretation in the context of the study’s early-stage design. Breakfree-2 is a single-arm, dose-escalation trial, and the interim efficacy findings are based on patients with sufficient follow-up for the relevant assessments. Larger and potentially controlled studies will be necessary to establish how zola-cel compares with existing therapies.
Early findings in highly active relapsing multiple sclerosis
Among the evaluable patients, six of seven individuals with highly active relapsing MS met the criteria for no evidence of disease activity (NEDA) at or beyond Week 26.
The NEDA assessment incorporates multiple measures of disease control, including the absence of relapses, disability progression and new MRI activity. Six of the seven evaluable patients met the overall NEDA criteria, while all patients in this subgroup achieved the individual reported outcomes of no relapse, no disability progression and no MRI activity.
These findings suggest that zola-cel may have the potential to suppress several key indicators of inflammatory MS activity following treatment. However, the result is based on a small group of seven evaluable patients and should be regarded as preliminary.
The study also assessed changes in disability using the Expanded Disability Status Scale (EDSS), a commonly used measure of neurological impairment in multiple sclerosis. All eight evaluable patients with haRMS demonstrated either stability or improvement in EDSS at or beyond Week 26.
The reported EDSS ranges were 3.0 to 5.5 among patients with haRMS and 4.0 to 6.0 among those with progressive MS. The findings indicate that the evaluable relapsing MS patients did not show worsening disability over the reported assessment period.
Although stability or improvement in EDSS is encouraging, disability outcomes in MS can vary over time, and a relatively short observation period cannot establish long-term protection against progression. Additional follow-up will be important to determine whether the early findings persist.
Progressive MS results show disability stability and no new MRI activity
The interim results also provide early evidence of potential clinical activity among patients with progressive multiple sclerosis, a group with substantial unmet medical needs.
Among the 24 evaluable patients with PMS, 22, or 92%, demonstrated stability or improvement in disability progression despite having experienced worsening disability at baseline. This finding suggests that most evaluable patients did not show further worsening during the reported follow-up period.
In addition, all 24 evaluable patients with progressive MS demonstrated no new MRI activity.
MRI is an important tool for monitoring multiple sclerosis because it can identify new or enlarging lesions associated with inflammatory disease activity. The absence of new MRI activity across the evaluated PMS group is therefore a potentially encouraging signal, particularly in a population that had experienced ongoing disease activity or worsening disability despite previous treatment.
Nevertheless, the absence of new MRI activity does not necessarily establish that the disease process has been halted. Progressive MS can involve gradual neurological deterioration even without prominent inflammatory MRI findings. Longer observation and more comprehensive clinical assessments will be needed to determine whether the reported stability translates into sustained functional benefit.
The distinction between relapsing and progressive disease is important when interpreting these results. Relapsing MS is often characterized by episodes of neurological worsening followed by partial or complete recovery, while progressive forms involve sustained disability accumulation. A treatment approach that addresses underlying immune mechanisms could potentially benefit both populations, but the nature and extent of that benefit must be established separately for each disease form.
Experts highlight the potential of CD19-directed CAR T-cell therapy
Jeffrey A. Cohen, M.D., Professor of Neurology and Staff Physician at the Mellen Center, Cleveland Clinic, said people living with relapsing and progressive multiple sclerosis need treatment options that address the underlying disease while helping control relapses and preserve function.
“These data suggest that CD19-directed CAR T cell therapy may offer a new approach to treating multiple sclerosis,” Cohen said. “While more research is needed, the potential to control relapses, stabilize disability and reduce reliance on disease-modifying medications is encouraging.”
His comments reflect the potential significance of exploring cellular therapies beyond their established applications in oncology. By targeting immune cells involved in autoimmune processes, CAR T-cell therapy is being investigated as a possible approach to achieving deeper and more durable immune modification.
Lynelle B. Hoch, president of the Cell Therapy Organization at Bristol Myers Squibb, said the company is exploring the potential for immune reset in patients with autoimmune diseases.
“BMS is at the forefront of cell therapy science, pioneering a new era by exploring the potential for immune reset in patients living with autoimmune diseases,” Hoch said.
She added that the Breakfree-2 data demonstrate the clinical potential of zola-cel in multiple sclerosis and highlight the opportunity to explore treatment-free remission for patients who have relied on chronic therapies for years. The company is advancing zola-cel with the goal of developing a potentially transformative treatment approach for autoimmune conditions.
The comments reflect the company’s broader strategy to investigate CAR T-cell technology in diseases beyond cancer. However, the current results remain preliminary, and treatment-free remission has not been established as a durable outcome for the wider MS population.
Further research will determine long-term benefit and risk
The Breakfree-2 interim results provide early evidence of clinical activity for zola-cel across highly active relapsing and progressive forms of multiple sclerosis. The findings include continued discontinuation of disease-modifying therapies among all patients treated at DL2, NEDA responses in most evaluable haRMS patients, stability or improvement in EDSS scores, and no new MRI activity among the evaluated PMS patients.
The safety findings were generally consistent with earlier Phase 1 data, with most CRS and ICANS events resolving within a short period. However, the Grade 4 ICANS event and the reported fatal septic pneumonia event underscore the importance of continued safety assessment.
Because Breakfree-2 is an early-stage, single-arm, dose-escalation study, its results cannot establish comparative effectiveness against approved MS therapies. The limited number of patients with evaluable efficacy outcomes and the varying duration of follow-up also mean that longer-term conclusions remain uncertain.
Future studies will need to determine whether the apparent disease-control effects persist, whether patients can remain off disease-modifying therapies over extended periods, and how the benefits and risks compare with existing treatment options. Researchers will also need to evaluate the potential effects on long-term disability progression, neurological function and quality of life.
Bristol Myers Squibb expressed its gratitude to the patients, families and investigators participating in the Breakfree-2 clinical trial. Their involvement is supporting the investigation of a new therapeutic strategy for people living with multiple sclerosis.
The data presented at MSToronto 2026 add to the growing exploration of CAR T-cell therapies as potential immune-reset treatments for autoimmune diseases. While the findings are encouraging, further clinical development will be essential to establish whether zola-cel can provide sustained disease control and a favorable benefit-risk profile for patients with relapsing and progressive multiple sclerosis.
About the Breakfree-2 Study
Breakfree-2 (NCT06220201) is a Phase 1, multicenter, single-arm, dose-escalation study evaluating the safety and efficacy of zolacabtagene autoleucel (zola-cel; BMS-986353), in patients with autoimmune neurological diseases: relapsing forms of multiple sclerosis, progressive forms of multiple sclerosis or refractory myasthenia gravis. Zola-cel is an investigational CD19-directed CAR T cell therapy that expresses the CD19 CAR and is manufactured using a next-generation process (NEX-T™). This platform uses an intentional five-day manufacturing process optimized so the CAR T cells reach a stable vector integration and early-differentiated phenotype prior to infusion.
Trial patients across cohorts follow a similar process: apheresis to collect T cells, after which the cells are manufactured into CD19 CAR T cells at specialized facilities utilizing the NEX-T manufacturing process. After undergoing lymphodepletion, patients receive a single infusion of zola-cel.
The primary endpoint is safety. Key secondary endpoints include number of patients meeting no evidence of disease activity criteria, number of patients with confirmed disability progression confirmed per EDSS, as well as pharmacokinetic outcomes.
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