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A participant in the phase I Breakfree-2 study of the investigational CAR-T therapy zola-cel died of septic pneumonia 44 days after treatment. The death followed high-dose cyclophosphamide given on day 41 to target circulating CAR-T cells, but investigators said the event’s cause is not fully understood and remains under investigation.
A participant in the phase I Breakfree-2 study of the investigational CAR-T therapy zolacabtagene autoleucel (zola-cel) died of septic pneumonia 44 days after treatment, according to a report presented at the 2026 joint ECTRIMS-ACTRIMS meeting. The death followed high-dose cyclophosphamide given on day 41; the cause of the event is not fully understood, and the case remains under investigation.
The patient had highly active relapsing multiple sclerosis. On day 17 after the zola-cel infusion, the participant developed extrapyramidal motor symptoms, including rigidity and tremor, and received intermittent corticosteroids and intravenous immunoglobulin. On day 41, clinicians gave 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.
Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center, presented the study findings and said the patient’s CAR-T cell expansion was in line with that of other participants. He said the death occurred after the analysis data cutoff of June 2026. The event was not reported as immune effector cell-associated neurotoxicity syndrome (ICANS), and the cause and relationship of the fatal infection to treatment have not been established in the report.
Breakfree-2 included 66 people with MS: 30 with highly active relapsing disease and 36 with progressive MS. The study’s primary goal was to evaluate safety and tolerability; efficacy was a secondary measure. The presentation reported cytokine release syndrome in 42.4% of participants, all resolving in a median of two days. ICANS occurred in 7.6%, mostly at grade 1 or 2; one grade 4 case resolved within four days after treatment with corticosteroids and anakinra. The reported fatality was the study’s only Grade 5 event.
Safety Questions for MS CAR-T
The death adds a serious safety finding to a small, early-stage trial of a treatment intended to alter immune activity in people with difficult-to-treat MS. For patients and clinicians, the case underscores that potential treatment effects must be weighed against risks, particularly when managing complications after cell therapy. It does not, on the information reported, establish that zola-cel caused the pneumonia or death.
The findings also arrive amid wider scrutiny of CAR-T therapies being studied for autoimmune disease. Bristol Myers Squibb paused its zola-cel program in September to evaluate safety findings, while Novartis reported three fatal ICANS cases in its autoimmune CAR-T trials of rapcabtagene autoleucel. Those reports concern a different product and do not establish a shared cause. The zola-cel study death was reported as not related to ICANS.
Potential efficacy signals in Breakfree-2 should also be read cautiously. The study was phase I, open-label and relatively small, and the reported follow-up was limited. Cohen said the results are not enough to establish how well zola-cel works or how its risks compare with other MS treatments.
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Breakfree-2 Trial Design and Findings
Breakfree-2 tested two dose levels of zola-cel in cohorts with highly active relapsing MS, progressive MS and refractory myasthenia gravis. The conference presentation covered the two MS groups. Before infusion, participants received lymphodepleting chemotherapy with fludarabine and cyclophosphamide, followed by a single dose of CAR-T cells. The report lists two dose levels, though the supplied material gives the same cell count for each, so the dose distinction cannot be clarified from those details.
The study included 12 people with primary progressive MS and 24 with non-relapsing secondary progressive MS. In the relapsing group, participants had experienced relapse while taking a high-efficacy disease-modifying therapy for at least six months. At the reported follow-up, all 60 patients treated at dose level 2 remained off disease-modifying therapies; nine had been followed for more than a year. Six of seven evaluated relapsing-MS patients met no-evidence-of-disease-activity criteria at week 26 or later. Among progressive-MS patients, the presentation reported no new MRI activity and stability or improvement in disability progression in 92%.
These observations come from a study designed primarily to assess safety and tolerability, not to prove clinical benefit. Cohen cautioned that CAR-T products differ and that results from small, uncontrolled, open-label trials require careful interpretation.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center
Cause of Death Still Under Review
The report does not establish whether zola-cel, cyclophosphamide, the patient’s underlying condition, or another factor caused or contributed to the septic pneumonia and death. Cohen said the event is still being investigated and its pathogenesis is not fully understood. The supplied account also does not give further details about the infection, the patient’s course after day 43, or any investigation findings released since the presentation.
The fatality occurred after the June 2026 data cutoff, so it was not part of the safety results summarized at that cutoff. The report says no other Grade 5 events occurred in Breakfree-2 or among 190 patients treated with zola-cel for autoimmune disease in phase I studies. That comparison does not resolve the cause of this death or determine the treatment’s overall safety. The status and timing of any next public update were not specified.
Investigation and Program Review
Investigators are continuing to examine the fatal event, according to Cohen. Further information may clarify the cause, whether treatment contributed, and whether the findings lead to changes in patient monitoring or study procedures. No conclusion on causality should be drawn until those details are available.
Bristol Myers Squibb paused its zola-cel program in September to evaluate safety findings. The supplied report does not say whether this death prompted that pause, whether the review has concluded, or when the company will provide an update. The study’s reported efficacy observations will also need longer follow-up and additional evidence before they can show whether the treatment offers durable benefit for people with MS.
Key Questions
What happened to the participant in the zola-cel study?
A participant with highly active relapsing MS developed motor symptoms 17 days after treatment, received high-dose cyclophosphamide on day 41, developed septic pneumonia on day 43 and died on day 44.
Has investigators’ report established that zola-cel caused the death?
No. Cohen said the event’s pathogenesis is not fully understood and remains under investigation. The report does not establish whether zola-cel, cyclophosphamide or another factor caused or contributed to the death.
Was the death attributed to ICANS?
No. The report says the death was not related to ICANS. A separate participant in the trial experienced a grade 4 ICANS event that resolved after treatment.
What did Breakfree-2 report about possible benefit?
The presentation reported that all 60 participants treated at dose level 2 remained off disease-modifying therapies at last follow-up. It also described disease-activity and disability findings, but the phase I study was small and open-label, so those results do not prove efficacy.
What happens next?
The fatal event remains under investigation. Bristol Myers Squibb had paused its zola-cel program in September to evaluate safety findings, but the report did not specify when the review will conclude or when further details will be released.
Source: rss
