Patient Death Reported in Multiple Sclerosis CAR-T Study

— 44 days after zola-cel treatment, MS patient dies of septic pneumonia

The investigational CD19-directed chimeric antigen receptor (CAR) T-cell therapy zolacabtagene autoleucel (zola-cel) showed the potential to treat people with highly active relapsing multiple sclerosis (MS) and progressive MS in a phase I study, but a fatal event occurred during the trial.

In the Breakfree-2 study, one death occurred due to septic pneumonia after a participant received high-dose cyclophosphamide, reported Jeffrey Cohen, MD, of the Cleveland Clinic Mellen Center. Cyclophosphamide was used as part of the original treatment protocol, and in this patient, was re-used later.

The death occurred after data cutoff. "The pathogenesis of that event is not fully understood," Cohen said at MSToronto2026, the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMSopens in a new tab or window) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

On day 17 after zola-cel administration, this patient, who had highly active relapsing MS, developed extrapyramidal motor symptoms including rigidity and tremor. The patient received intermittent corticosteroids and IV immunoglobulin (IVIG).

On day 41, the patient received high-dose cyclophosphamide to target circulating CAR-T cells, as no alternative cause was identified. "Cell expansion in this patient was in line with expansion in the other participants," Cohen noted. On day 43, septic pneumonia developed, and on day 44, the patient died.

This event is still being investigated, Cohen said. No other Grade 5 events were reported in the trial or in any of 190 patients treated with zola-cel for autoimmune disease in phase I studies.

In September, developer Bristol Myers Squibb paused its zola-cel programopens in a new tab or window to evaluate safety findings around the same time that Novartis reported three fatal cases of immune effector cell-associated neurotoxicity syndrome (ICANS) in its CAR-T autoimmune trials of rapcabtagene autoleucel (rap-cel). The death in the zola-cel study was not related to ICANS.

Many MS patients have ongoing disease activity or disability worsening despite available therapies, Cohen observed. "Given the role of autoreactive B cells in MS pathogenesis, CD19-directed CAR-T cells -- through their ability to produce deep tissue depletion of B cells followed by reconstitution -- have the potential to induce an immune reset and durable disease control," he said.

Breakfree-2opens in a new tab or window was designed to evaluate zola-cel in three cohorts: one with highly active relapsing MS, one with progressive MS, and one with refractory myasthenia gravis. The presentation focused on the first two groups only, with a data cutoff of June 2026.

The study tested two dose levels of zola-cel. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by an infusion of a single dose of zola-cel, either 5×10⁶ CAR-T cells (dose level 1) or 5×10⁶ CAR-T cells (dose level 2).

The MS cohorts totaled 66 patients -- 30 with highly active relapsing MS, and 36 with progressive MS. The highly active group had relapse while on a high-efficacy disease-modifying therapy (DMT) for at least 6 months. The progressive group included 12 people with primary progressive and 24 with non-relapsing secondary progressive MS.

The study's primary endpoint was safety and tolerability, with efficacy as a secondary endpoint. Most adverse events were brief and generally consistent with previously reported zola-cel phase 1 clinical trial data, Cohen noted.

Overall, 42.4% of Breakfree-2 participants had cytokine release syndrome; 36.4% had grade 1 and 6.1% had grade 2. All resolved in a median of 2 days.

A total of 7.6% of patients had ICANS, mostly grade 1 or 2, which resolved in a median of 2 days. One grade 4 ICANS event occurred in a patient with progressive MS; it was treated with corticosteroids and anakinra (Kineret) and resolved within 4 days.

At last follow-up, all 60 patients treated at dose level 2 remained off DMTs, including nine patients who had been followed for more than 12 months. Six of seven highly active relapsing MS patients who were evaluated for no evidence of disease activity (NEDA) met criteria at week 26 or later. Patients with progressive MS had no new MRI activity. Despite earlier worsening at baseline, 92% of progressive MS patients had stability or improvement in disability progression.

The experience of using CAR T-cell therapy in autoimmune disease has been limited to date. "We're still learning some of the nuances of CAR-T therapy. They can't all be lumped together. Each cell product is a little bit different, and they have their own attributes," Cohen told MedPage Today.

"There's some enticing evidence of benefit, although these trials are still small with relatively short follow-up, and for the most part, are uncontrolled and open-label," he said. "So, efficacy results have to be interpreted with caution."