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A participant with highly active relapsing multiple sclerosis died of septic pneumonia 44 days after receiving the experimental CAR-T therapy zola-cel in the Breakfree-2 study. The death followed high-dose cyclophosphamide given on day 41, and investigators say its cause is not fully understood. The event was reported after the study’s June 2026 data cutoff.
A participant with highly active relapsing multiple sclerosis died of septic pneumonia 44 days after receiving the investigational CAR-T therapy zolacabtagene autoleucel, or zola-cel, in the phase I Breakfree-2 study. The death occurred after the study’s June 2026 data cutoff, and investigators said the event’s cause is not fully understood.
Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center, reported the case at MSToronto2026, a joint meeting of the European and Americas committees for multiple sclerosis research. According to the presentation, the participant developed rigidity and tremor on day 17 after zola-cel and received intermittent corticosteroids and intravenous immunoglobulin. On day 41, the patient was given high-dose cyclophosphamide to target circulating CAR-T cells after clinicians identified no alternative cause for the symptoms. Septic pneumonia developed on day 43, and the patient died the following day.
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), according to the report. The fatal event is still being investigated. The presentation said no other Grade 5 events had been reported in Breakfree-2 or among 190 people treated with zola-cel for autoimmune disease in phase I studies; that comparison does not explain the cause of this death.
Breakfree-2 enrolled 66 people in its multiple sclerosis cohorts: 30 with highly active relapsing MS and 36 with progressive MS. The trial’s primary focus was safety and tolerability, with efficacy assessed as a secondary endpoint. The reported safety and outcome figures reflect the data cutoff in June 2026 and do not include the death, which occurred later.
Safety Questions for Zola-Cel
The death puts the safety of an experimental cell therapy under close scrutiny, particularly because high-dose cyclophosphamide was administered shortly before the pneumonia developed. The available account establishes the sequence of events, but it does not establish that zola-cel or cyclophosphamide caused the death. Cohen said the event’s pathogenesis was not fully understood, and the investigation is ongoing.
The case also matters because CAR-T treatment is being studied as a potential option for people whose MS remains active or whose disability worsens despite existing therapies. The therapy is designed to deplete B cells, which are involved in MS, but potential benefit must be weighed against serious risks and the demands of treatment and monitoring. A single event cannot determine the overall risk, yet it is significant safety information for researchers, regulators and patients following the program.
Interpretation of both safety and possible benefit is limited by the trial’s early phase and relatively small groups. The study was not designed to establish comparative effectiveness, and the reported efficacy measures were secondary. The fatal case should be considered alongside the wider safety record as investigators clarify what happened.
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Trial Design and Earlier Safety Data
Breakfree-2 tested two dose levels of zola-cel in people with highly active relapsing MS and progressive MS, as well as a separate cohort with refractory myasthenia gravis. The meeting presentation focused on the MS groups. Participants received lymphodepleting chemotherapy with fludarabine and cyclophosphamide before a single zola-cel infusion. The report lists the two dose levels as 5×10⁶ CAR-T cells each.
In the data available through June 2026, cytokine release syndrome was reported in 42.4% of participants: 36.4% had grade 1 and 6.1% had grade 2 events, which resolved in a median of two days. ICANS was reported in 7.6%, mostly at grade 1 or 2, also resolving in a median of two days. One participant with progressive MS had grade 4 ICANS; it resolved within four days after treatment with corticosteroids and anakinra.
The presentation also reported early signals of disease control: all 60 patients treated at dose level 2 were off disease-modifying therapies at last follow-up, and nine had been followed for more than 12 months. Six of seven evaluated participants with highly active relapsing MS met no-evidence-of-disease-activity criteria at week 26 or later. These findings are early and uncontrolled, and Cohen cautioned that they should be interpreted carefully.
In September, Bristol Myers Squibb paused its zola-cel program to evaluate safety findings, according to the source report. Around the same time, Novartis reported three fatal cases of ICANS in its autoimmune CAR-T trials of rapcabtagene autoleucel. Those cases involved a different product; the Breakfree-2 death was reported as not related to ICANS.
“The pathogenesis of that event is not fully understood.”
— Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center
Cause and Safety Review Remain Open
The report does not establish whether the pneumonia was caused by the CAR-T treatment, the high-dose cyclophosphamide, another factor, or a combination of causes. It also does not provide further clinical details about the infection, the patient’s condition between treatment and symptom onset, or the findings of any completed review. Cohen said the event is still being investigated.
The June 2026 data cutoff predates the death, so the presentation’s earlier adverse-event totals do not include it. The source does not specify whether the trial protocol, enrollment, or other treatment decisions have changed as a result of the case. Nor does it report a final determination by the sponsor or regulators.
Investigators to Clarify the Fatal Event
The immediate next step is the ongoing investigation into the participant’s death and the circumstances surrounding the septic pneumonia and day-41 cyclophosphamide treatment. Any further conclusions about cause, relatedness to treatment, or protocol changes will depend on findings that were not available in the meeting report.
Researchers and the sponsor will also need to assess the case alongside longer follow-up from Breakfree-2 and the broader safety experience with zola-cel. The study’s next reported safety updates may help clarify whether the event changes the risk assessment for the MS cohorts. Until those details are reported, the cause of death and its implications for the program remain unsettled.
Key Questions
What happened to the participant in the zola-cel study?
The participant 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. The event is under investigation.
Has investigators’ identified what caused the death?
No. Jeffrey Cohen said the event’s pathogenesis was not fully understood. The report does not establish whether the death was caused by zola-cel, cyclophosphamide or another factor.
Was the death reported as an ICANS case?
No. The report said the death was not related to ICANS. It separately described one grade 4 ICANS event in a participant with progressive MS, which resolved after treatment.
How many people with MS were included in Breakfree-2?
The two MS cohorts included 66 participants: 30 with highly active relapsing MS and 36 with progressive MS. The June 2026 data cutoff came before the reported death.
Do the early results show that zola-cel is effective for MS?
The study reported early signs of disease control, but it was a small phase I trial with efficacy as a secondary endpoint. Cohen said the results should be interpreted cautiously because the trials were largely uncontrolled and open-label, with relatively short follow-up.
Source: rss
