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A participant in the phase I Breakfree-2 study of CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment. The investigator said the cause of the event is not fully understood and that it remains under investigation; the death was not reported as ICANS. The trial also reported safety and early disease-activity findings in 66 participants with multiple sclerosis.
A participant in a phase I study of the investigational CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment, according to findings presented at MSToronto2026. The death followed high-dose cyclophosphamide given to target circulating CAR-T cells, but investigator Jeffrey Cohen said the event’s pathogenesis is not fully understood and remains under investigation.
The participant had highly active relapsing multiple sclerosis and developed rigidity and tremor on day 17 after receiving zola-cel. The patient was treated intermittently with corticosteroids and intravenous immunoglobulin. On day 41, clinicians administered high-dose cyclophosphamide to target circulating CAR-T cells after identifying no alternative cause for the symptoms, Cohen reported. Septic pneumonia developed on day 43, and the patient died the following day.
Cohen, of the Cleveland Clinic Mellen Center, presented the findings from the Breakfree-2 study at a joint meeting of the European and Americas committees for multiple sclerosis research. The reported death occurred after the study’s June 2026 data cutoff. Cohen said the participant’s CAR-T cell expansion was in line with that seen in other participants. The death was not attributed to immune effector cell-associated neurotoxicity syndrome (ICANS), and investigators have not established the event’s cause.
The study’s multiple sclerosis groups included 66 participants: 30 with highly active relapsing MS and 36 with progressive MS. The trial’s primary focus was safety and tolerability, with efficacy as a secondary endpoint. The presentation reported cytokine release syndrome in 42.4% of participants, all resolving in a median of two days; 7.6% had ICANS, mostly grade 1 or 2. One grade 4 ICANS event in a participant with progressive MS resolved within four days after treatment with corticosteroids and anakinra.
Safety Questions for Zola-Cel
The death adds a serious safety event to evidence from an early-stage, small study of a cell therapy being tested for MS. CAR-T treatments are designed to alter immune-cell activity, and the reported use of cyclophosphamide to target CAR-T cells after neurological symptoms emerged makes the sequence of events relevant to how researchers assess risks and manage complications. The report does not establish that zola-cel or cyclophosphamide caused the fatal infection.
For patients and clinicians, the early signs of potential benefit must be weighed against the limits of the data and the unresolved safety questions. Cohen said that, at the last follow-up, all 60 people treated at dose level 2 remained off disease-modifying therapies; some participants with progressive MS had stable or improved disability measures. These are interim findings from an uncontrolled phase I study, not proof that the therapy is effective or that benefits will persist. Bristol Myers Squibb had paused its zola-cel program in September to evaluate safety findings.
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Breakfree-2 Trial and Prior Safety
Breakfree-2 was designed to study zola-cel in three groups, including participants with highly active relapsing MS, progressive MS and refractory myasthenia gravis. The conference presentation discussed the two MS groups. Participants received lymphodepleting chemotherapy with fludarabine and cyclophosphamide before a single zola-cel infusion. Cyclophosphamide was also administered again to the participant who later died, according to Cohen’s presentation.
The presentation reported no other Grade 5 events in Breakfree-2 and none among 190 people treated with zola-cel for autoimmune disease in phase I studies, as described by the investigator. That broader count does not resolve the cause of this death. The report also distinguished it from fatal ICANS cases reported in other CAR-T autoimmune trials: the zola-cel participant’s death was not reported as ICANS. Cohen cautioned that CAR-T products differ and should not be treated as interchangeable.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, Cleveland Clinic Mellen Center
Cause of Fatal Infection Unresolved
The available report does not establish whether the septic pneumonia resulted from zola-cel, the later high-dose cyclophosphamide, the patient’s clinical condition, or a combination of factors. Cohen said the event is still being investigated and that its pathogenesis is not fully understood. Further details about the investigation, including whether additional safety measures will follow, were not provided in the presentation summary.
The trial results are also limited by their phase I design and relatively short follow-up. The account does not provide enough information to determine how the fatal event changes the overall risk assessment or the program’s future status. It is not clear from the report when investigators or the sponsor will publish a fuller safety analysis.
Safety Review and Trial Status
Investigators are continuing to examine the death, according to Cohen. Bristol Myers Squibb’s program pause, announced in September to evaluate safety findings, means the therapy’s development status remains an important point to watch. The source report does not give a date for a decision on resuming the program or for release of further findings.
Any subsequent study update may clarify the event’s cause, whether the trial protocol or monitoring has changed, and how the sponsor plans to proceed. Until those details are reported, the early disease-activity observations should be read alongside the unresolved fatal event and the study’s limited size and follow-up.
Key Questions
What happened in the zola-cel study?
A participant with highly active relapsing MS developed rigidity and tremor after treatment, later received high-dose cyclophosphamide, developed septic pneumonia on day 43 and died on day 44 after zola-cel administration.
Was the death attributed to ICANS?
No. The report says the death was not related to ICANS. The event’s cause has not been determined, and investigators are still examining it.
How many people with MS were included in the study presentation?
The two MS groups included 66 participants: 30 with highly active relapsing MS and 36 with progressive MS. The presentation focused on those groups, not the study’s myasthenia gravis cohort.
Did the study show that zola-cel is effective for MS?
The presentation included early observations, such as participants remaining off disease-modifying therapies and measures of disease activity. But Breakfree-2 was a small, early-phase study, and Cohen cautioned that efficacy findings from trials that are largely uncontrolled and open-label should be interpreted carefully.
What happens to the zola-cel program now?
Bristol Myers Squibb had paused the program in September to evaluate safety findings. The report does not state when the pause will end or whether the study protocol will change; the fatal event remains under investigation.
Source: rss
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