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A participant in the Breakfree-2 phase I study of the experimental CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment. The death followed high-dose cyclophosphamide given on day 41 and is under investigation; the researcher said its cause is not fully understood. The trial also reported other serious immune-related events, while early efficacy findings remain preliminary.
A participant in a phase I study of the experimental CD19-directed CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment, according to findings presented at the MSToronto2026 meeting. Study investigator Jeffrey Cohen of the Cleveland Clinic said the cause of the event is not fully understood and remains under investigation; the death was reported after the study’s June 2026 data cutoff.
The patient had highly active relapsing multiple sclerosis. On day 17 after receiving zola-cel, the participant developed extrapyramidal motor symptoms, including rigidity and tremor, and was treated intermittently with 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 had been identified. Septic pneumonia developed on day 43, and the patient died the following day.
Cyclophosphamide was part of the original treatment protocol and was used again in this case, Cohen reported. He said the patient’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), a known potential complication of CAR-T treatment. Cohen said the event is still being investigated and that its pathogenesis is not fully understood.
The presentation covered 66 people with MS in Breakfree-2: 30 with highly active relapsing disease and 36 with progressive disease. The study’s primary focus was safety and tolerability, with efficacy assessed as a secondary endpoint. The report said no other Grade 5 events were reported in the trial or among 190 people treated with zola-cel for autoimmune diseases in phase I studies. That broader figure does not establish the risk of rare events, and the study remains small.
Safety Questions for MS CAR-T
The death puts a serious safety event at the center of an early trial of a treatment approach that may carry different risks from established multiple sclerosis medicines. CAR-T cells are engineered to target immune cells; in autoimmune disease research, the aim is to reduce B cells and potentially reset parts of the immune system. But a fatal infection after treatment and additional immune-related events make careful safety monitoring essential as researchers evaluate whether possible benefits justify the risks.
Breakfree-2’s early results are not proof that zola-cel controls MS. Researchers reported encouraging measures among some participants, but the study is a phase I trial, and the report described the evidence as based on small, mostly uncontrolled, open-label studies with relatively short follow-up. The fatal event also occurred after the June data cutoff, so it was not part of the safety snapshot presented for that date.
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What Breakfree-2 Tested
Breakfree-2 was designed to study zola-cel in people with highly active relapsing MS, progressive MS and refractory myasthenia gravis. The conference presentation focused on the two MS groups. Participants received lymphodepleting chemotherapy, including fludarabine and cyclophosphamide, followed by a single zola-cel infusion. The source report lists two dose levels, but gives the same cell count for both, so the distinction between the doses is unclear.
Among reported outcomes, 42.4% experienced cytokine release syndrome, reported as Grade 1 in 36.4% and Grade 2 in 6.1%; these cases resolved in a median of two days. ICANS was reported in 7.6%, mostly Grade 1 or 2, also resolving in a median of two days. One Grade 4 ICANS event in a participant with progressive MS resolved within four days after treatment with corticosteroids and anakinra.
At the last follow-up, all 60 participants treated at dose level 2 were reported to be off disease-modifying therapies, including nine followed for more than 12 months. Six of seven assessed participants with highly active relapsing MS met no-evidence-of-disease-activity criteria at week 26 or later. The report also said there was no new MRI activity among participants with progressive MS and that 92% had stable or improved disability progression. These are preliminary study findings, not comparisons with an untreated group.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, Cleveland Clinic Mellen Center
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Cause and Safety Remain Under Review
The available report does not establish whether the septic pneumonia was caused by zola-cel, cyclophosphamide, another aspect of treatment, or a combination of factors. The patient received high-dose cyclophosphamide three days before pneumonia developed, but the sequence alone does not show causation. Investigators have not reported a final explanation, and the event occurred after the study’s stated data cutoff.
The report also does not provide a detailed account of the patient’s clinical course after pneumonia began, or a final assessment of the event’s relationship to the therapy. Bristol Myers Squibb paused its zola-cel program in September to evaluate safety findings, according to the report, but it does not specify whether this death was the reason for that pause. The number of participants and length of follow-up limit what can be concluded about uncommon risks.
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Investigators Continue the Safety Review
The immediate next step is the ongoing investigation into the death and the circumstances surrounding the repeat dose of cyclophosphamide. The report does not give a date for a final finding or say when the study’s safety assessment will be updated. Bristol Myers Squibb’s previously reported pause of the zola-cel program means further development is subject to its safety evaluation.
Any later study updates will need to clarify the suspected cause of the pneumonia, whether the event is considered related to treatment, and how the safety profile compares across zola-cel dose groups and patient populations. Until more data are available, the reported disease activity and disability findings remain preliminary, while the fatal event remains under review.
Key Questions
What happened to the participant in the zola-cel study?
The participant developed motor symptoms on day 17 after treatment, received high-dose cyclophosphamide on day 41, developed septic pneumonia on day 43 and died on day 44. Investigators have not established the cause of the event.
Was the death attributed to ICANS?
No. The report says the death was not related to ICANS. It identifies septic pneumonia as the cause of death and says the event’s pathogenesis remains under investigation.
How many people with MS were included in Breakfree-2?
The study included 66 participants with MS: 30 with highly active relapsing MS and 36 with progressive MS. The presentation reported results for those two groups.
Do the study results show that zola-cel is effective for MS?
Not conclusively. The reported activity and disability findings are early results from a phase I study, with efficacy as a secondary endpoint. Cohen cautioned that studies were small, mostly uncontrolled and open-label, with relatively short follow-up.
What is known about zola-cel’s development status?
The report says Bristol Myers Squibb paused its zola-cel program in September to evaluate safety findings. It does not provide a timetable for resuming development or for a final investigation into the death.
Source: rss
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