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A participant with highly active relapsing multiple sclerosis died of septic pneumonia 44 days after receiving the investigational CAR-T therapy zola-cel in the Breakfree-2 study. The death followed high-dose cyclophosphamide given on day 41, and investigators say the event’s cause is not fully understood. The trial presentation also reported other safety and early efficacy findings, which remain preliminary.
A participant in the Breakfree-2 phase I study of the investigational CAR-T therapy zolacabtagene autoleucel (zola-cel) died of septic pneumonia 44 days after treatment, according to a presentation by Cleveland Clinic neurologist Jeffrey Cohen. The death occurred after the study’s June 2026 data cutoff, and the cause is still being investigated; the reported fatal event was not attributed to ICANS, a neurological complication associated with some immune-cell therapies.
The patient, who had highly active relapsing multiple sclerosis, developed rigidity and tremor on day 17 after the zola-cel infusion. Cohen said the patient received intermittent corticosteroids and intravenous immunoglobulin. On day 41, clinicians administered high-dose cyclophosphamide to target circulating CAR-T cells after no alternative cause for the symptoms was identified. Septic pneumonia developed on day 43, and the patient died the following day.
Cyclophosphamide was included in the original treatment protocol and was used again in this case, according to the report. Cohen said the patient’s CAR-T cell expansion was in line with that seen in other participants. He told the meeting that the event’s pathogenesis is not fully understood and that it remains under investigation. The report does not establish whether the infection, the treatment, the patient’s neurological symptoms or a combination of factors caused the death.
The study presentation covered 66 people with MS: 30 with highly active relapsing disease and 36 with progressive MS. The trial’s primary aim was to assess safety and tolerability, with efficacy as a secondary measure. Separately, the presentation reported cytokine release syndrome in 42.4% of participants, all described as resolving, and ICANS in 7.6%; most ICANS cases were grade 1 or 2. One grade 4 ICANS case in a progressive-MS participant resolved after treatment, Cohen reported.
Safety Findings in the Zola-Cel Trial
The death adds a serious safety event to evidence about an experimental treatment being studied for people with MS whose disease may remain active despite existing therapies. CAR-T treatment involves substantial immune-cell intervention, and the case included neurological symptoms, immune-directed treatment and a later infection. The available account does not determine how those events were related, making the ongoing investigation important for understanding risks and possible changes to trial monitoring or treatment procedures.
The presentation also included early signs of potential benefit, but these do not resolve the safety questions. Cohen said that all 60 patients treated at dose level 2 were off disease-modifying therapies at last follow-up, and reported MRI and disability findings in the progressive-MS group. Those results come from a small, early-stage study with limited follow-up and no control group, so they cannot establish that zola-cel caused improvement or is more effective than available care.
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Breakfree-2 Study Design and Findings
Breakfree-2 was designed to study zola-cel in three groups: people with highly active relapsing MS, people with progressive MS and people with refractory myasthenia gravis. The presentation described the two MS groups. Participants received lymphodepleting chemotherapy with fludarabine and cyclophosphamide before a single zola-cel infusion. The report says two dose levels were studied, though the supplied account lists the same cell number for both and does not clarify that detail.
The highly active relapsing-MS group had experienced a relapse while taking a high-efficacy disease-modifying therapy for at least six months. The progressive-MS group included 12 people with primary progressive MS and 24 with non-relapsing secondary progressive MS. Cohen said most adverse events were brief and generally consistent with earlier phase I zola-cel data. At the last follow-up, six of seven evaluated patients in the highly active group met criteria for no evidence of disease activity at week 26 or later; the presentation also reported no new MRI activity in progressive MS.
The findings were presented at MSToronto2026, a joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis and the Americas Committee for Treatment and Research in Multiple Sclerosis. The report also noted that Bristol Myers Squibb paused its zola-cel program in September to evaluate safety findings. The supplied account does not state whether that pause was specifically triggered by this death.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center
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Cause of the Fatal Infection
The relationship between zola-cel, the patient’s neurological symptoms, high-dose cyclophosphamide and the septic pneumonia has not been established in the reported findings. Cohen said the cause is not fully understood and the event remains under investigation. The account does not provide further clinical details about the infection or an investigator conclusion on whether treatment contributed.
The report also does not give a revised safety analysis incorporating the death, explain whether the event changed trial procedures, or specify the status of enrollment after the company’s program pause. The pause was reported in September, but the available information does not establish its direct connection to this participant’s case. The early efficacy observations are also limited by short follow-up and the study’s open-label, uncontrolled design.
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Investigation and Program Review
Investigators are continuing to examine the fatal event, according to Cohen. Further information may clarify the clinical sequence, the role of cyclophosphamide and whether the case affects the assessment of zola-cel’s risks. Bristol Myers Squibb’s reported pause to evaluate safety findings is another development to watch; the supplied report does not give a timeline for a decision on the program.
Any future trial updates will need to show how safety findings are assessed alongside longer-term outcomes. Until more data are reported, the death should be understood as a serious event under investigation—not as proof of a specific cause or a settled conclusion about zola-cel’s overall safety. The study’s early efficacy results likewise remain preliminary.
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Key Questions
What happened to the participant in the zola-cel study?
The participant developed rigidity and tremor 17 days after treatment, received intermittent corticosteroids and IVIG, and was given high-dose cyclophosphamide on day 41. Septic pneumonia developed on day 43, and the patient died on day 44.
Do investigators know what caused the death?
No cause has been established in the reported findings. Jeffrey Cohen said the event’s pathogenesis is not fully understood and remains under investigation.
Was the death reported as an ICANS event?
No. The report says the death was not related to ICANS. The patient had earlier motor symptoms, but the account does not establish their cause or a link to the fatal infection.
What did the study report about zola-cel’s potential benefits?
The presentation reported that six of seven evaluated patients with highly active relapsing MS met no-evidence-of-disease-activity criteria at week 26 or later, and that progressive-MS participants had no new MRI activity. These are early findings from a small, uncontrolled study and require cautious interpretation.
What happens next for the zola-cel program?
The fatal event is under investigation, and Bristol Myers Squibb was reported to have paused its zola-cel program in September while evaluating safety findings. The available report does not give a date for a decision on the pause or additional trial results.
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