Patient dies in early test of engineered immune cells for MS, maker says

Two months ago, Biohack reported that Novartis halted 8 trials of a similar cell therapy after 3 deaths, and that Bristol Myers Squibb paused enrollment in its own program. Now Bristol Myers has disclosed a death of its own: a person with multiple sclerosis (MS) who died after receiving its experimental treatment in an early-stage study.¹

What happened

Bristol Myers Squibb said a patient in its Breakfree-2 study died of septic pneumonia, a severe lung infection that spreads through the body, 44 days after being infused with zolacabtagene autoleucel, or zola-cel.² The study is a Phase 1 trial, the first small test of a treatment in people, mainly meant to check safety.²

Zola-cel is a CAR-T therapy. Doctors collect a patient’s own immune cells, called T cells, and engineer them in a lab to seek out and remove B cells, another type of immune cell. The goal is to wipe out B cells and give the immune system a kind of reset.³ In MS, the immune system attacks the brain and spinal cord.

According to the company, the patient had highly active relapsing MS, the form where symptoms flare and then ease. The person developed motor symptoms, problems with movement, late after treatment. The company said these were not caused by ICANS, a known nerve-related side effect of CAR-T therapies, and did not improve with steroid drugs or intravenous immunoglobulin, an antibody treatment.¹ Doctors then gave a high dose of cyclophosphamide, a strong drug that suppresses the immune system.³ The patient developed septic pneumonia and died the next day.¹

The company said the patient’s engineered cells multiplied in the body at levels similar to other people in the study.³ The death occurred after the study’s data cutoff, the date after which new results were not included in the analysis.¹

The evidence so far

The disclosure came alongside early results from Breakfree-2, ahead of a presentation at the ACTRIMS-ECTRIMS meeting, a major MS conference.⁴ The study included 66 people whose MS stayed active or whose disability kept getting worse despite earlier treatments.¹

On safety, which was the study’s main goal, Bristol Myers said most side effects in the MS groups were short-lived and went away, in line with earlier data on the therapy.¹ Cytokine release syndrome, a fever-like immune overreaction common after CAR-T, occurred in 42.4% of the 66 patients. ICANS affected 7.6%, and nearly all cases cleared up within days.¹ One more serious ICANS case, in a patient with progressive MS, resolved within four days, the company said.¹

The company also reported early signs about the disease itself:

• Among 24 people with progressive MS who could be assessed, 22 had stable or improved disability scores despite worsening before treatment, and all 24 showed no new activity on MRI scans.³
• Among people with at least six months of follow-up, six of seven with highly active relapsing MS showed no evidence of disease activity.¹
• All 60 patients who got the higher dose had stayed off their regular MS drugs at the last check, including nine followed for more than a year, according to one report.¹

Bristol Myers says no other deaths have been reported among the 190 people treated in its early studies of zola-cel across autoimmune diseases.¹ Investors reacted: the company’s shares fell 2% on the day of the disclosure.¹

What it does not show yet

These results come from the company and have not been published in a peer-reviewed journal. The study has no comparison group, and long-term follow-up is limited, so the early findings on disease control remain preliminary.³ Without a comparison group, it is not possible to tell how much of the stability seen is due to the treatment.

Safety was the main goal, but the company’s announcement does not say whether that goal was formally met. It describes the safety profile as consistent with earlier zola-cel data.³ It also does not explain how the late motor symptoms, the strong immune-suppressing drug and the fatal infection relate to one another, beyond the order of events.¹ The Pharma Digest noted that details are thin.⁴

A single death in a small study cannot show how often such an outcome would happen in a larger group of patients.

How it ties to the earlier pause

In late summer, Bristol Myers paused enrollment in some of its CAR-T trials for autoimmune diseases after seeing short-lived inflammatory side effects that went away. It said at the time it was reviewing safety data “out of an abundance of caution.”⁵ Reports differ slightly on timing: one describes the pause as happening in September.¹

The company says the new death was unrelated to that pause.² A company spokesperson told Bloomberg the death happened after the decision to pause enrollment.¹ Bristol Myers said it intends to keep developing zola-cel, but its announcement did not say whether enrollment has resumed or describe steps taken to address the safety events.³

How it fits the field

The news adds to growing safety questions about using CAR-T, first developed for blood cancers, in autoimmune diseases.¹ Novartis paused eight trials of its similar therapy, rapcabtagene autoleucel (rap-cel), after three participants died from immune effector cell-associated hemophagocytic syndrome (IEC-HS), a rare but potentially life-threatening inflammatory reaction.⁵ Those trials covered lupus, MS, rheumatoid arthritis and myasthenia gravis.⁵ Novartis said it was working with independent data committees to find the causes.⁵ At the time, the cause of IEC-HS in those cases was still being investigated, and some industry analysts suggested fast manufacturing processes or certain patient traits might raise risk.⁵

The Bristol Myers death was from an infection, not IEC-HS, according to the company’s account.¹ The Pharma Digest argued that moving CAR-T from cancer into autoimmune disease asks patients with manageable conditions to accept the risk of lymphodepletion, a step that wipes out immune cells before the infusion, so the bar for tolerable side effects is far higher.⁴ It also called two safety events in about two months a pattern that investors and regulators will notice.⁴

Zola-cel works differently from the B-cell-depleting MS drugs already approved, which target a molecule called CD20 rather than CD19.³

Who is behind it

Zola-cel is developed and paid for by Bristol Myers Squibb, which also reported the results and the death.³ All the safety and early benefit figures above come from the company’s own disclosure, as relayed by industry news outlets.¹³

What to watch next

• Whether Bristol Myers restarts enrollment in its zola-cel studies, and what safety changes it describes.³
• The full Breakfree-2 data as presented at ACTRIMS-ECTRIMS, and any later journal publication.⁴
• The outcome of Novartis’s safety review of its paused trials, which other companies are watching for lessons on patient selection, manufacturing and monitoring.⁵