‘Off-the-Shelf’ CAR T-Cell Tx Shows Early Safety in MS

TORONTO — The first allogeneic CD19-directed chimeric antigen receptor (CAR) T-cell therapy to be evaluated in progressive multiple sclerosis (MS) showed no serious safety signals in early phase 1 results.Among 18 patients with refractory progressive MS, treatment with azercabtagene zapreleucel (azer-cel) produced no dose-limiting toxicities (DLTs), severe cytokine release syndrome, significant neurotoxicity, or graft-vs-host disease.Disability scores remained stable or improved in all evaluable patients at 90 days, and three patients improved by two or more points on the Expanded Disability Status Scale (EDSS), including one patient with a 4-point gain.While other CAR T-cell therapies use autologous cells, which involve the extraction, manipulation, and reinfusion of a patient’s own cells, the current therapy is allogeneic, so it uses cells from healthy donors.This approach allows cells to be mass-produced and stored in advance, said study investigator Daniel Ontaneda, MD, PhD, professor of neurology at Cleveland Clinic Lerner College of Medicine and the Mellen Center for Multiple Sclerosis in Cleveland.“Essentially, you can create a lot of these cells…and then just administer them,” he told Medscape Medical News.Azer-cel was first developed as a cancer treatment, and research cited by Ontaneda showed it has been tested in more than 130 oncology patients, providing safety data that predate its use in MS.The study was presented on October 23 at the 10th Joint Americas Committee for Treatment and Research in Multiple Sclerosis-European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS) 2026.Exploring an ‘Off-the-Shelf’ OptionCurrently available disease-modifying therapies for MS are effective at reducing relapses and preventing new lesions. However, disability can continue to accumulate independently of relapse activity, and few agents are approved for purely progressive forms of the disease, said Ontaneda.“CD20 monoclonal antibodies are phenomenal at controlling acute inflammation in MS, so they control relapses, and they control formation of new T2 lesions,” he said.Many patients continue to worsen, though, possibly because of chronic inflammation or inflammation behind the blood-brain barrier. “I think the window of opportunity here is that there’s a portion of inflammation that CD20 therapies given peripherally are not covering,” he said.CAR T cells may produce a more profound effect on B cells, Ontaneda said. Unlike peripherally administered monoclonal antibodies, they may also enter the central nervous system and potentially target B cells in areas less accessible to existing therapies. There is also some suggestion that CAR T-cell therapy could induce an immune system “reset.”The researchers evaluated six different doses, administered by infusion. The primary endpoint was DLTs associated with cell therapy, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), graft-vs-host disease, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome.The study included 26 adults with primary progressive, active secondary progressive, or nonactive secondary progressive MS. They had a median age of 51.5 years, and approximately 50% were female, with an average disease duration of about 9 years.Participants had substantial disability at baseline, with a median EDSS score of 6, indicating the need for assistance in walking. All participants were receiving high-efficacy anti-CD20 therapy.No DLTs or high-grade CAR T-cell-associated toxicities were reported through day 28 of the study. Two cases of low-grade CRS occurred, one grade 1 and one grade 2. ICANS was reported in two patients, both with grade 1 events.“In these cases, the grade wasn’t very high, and those individuals recovered well,” noted Ontaneda.There were a total of 11 patients with treatment-emergent adverse events of grade 3 or higher, and four serious adverse events were reported. There was no consistent increase in adverse event frequency at higher dose levels.A New Window of Opportunity?Treatment produced peripheral B-cell depletion in 25 of 26 patients, along with an early signal of B-cell reduction in the cerebrospinal fluid (CSF). As B cells returned, they were enriched for transitional and naive phenotypes, with fewer switched memory B cells.The problem, though, is that many patients continue to worsen, possibly due to chronic inflammation or inflammation behind the blood-brain barrier, said Ontaneda. “I think the window of opportunity here is that there’s a portion of inflammation that CD20 therapies given peripherally are not covering.”There’s also some suggestion that CAR T-cell therapy might produce something of an immune reset, he added.In terms of clinical outcomes, most participants were either stable or improved at day 90. This was true for 16 of 18 patients on the EDSS, 16 of 17 on the Timed 25-Foot Walk, 17 of 18 on the 9-Hole Peg Test, and 14 of 18 improved on the Symbol Digit Modalities Test, which assesses cognitive function.The effects appeared to be durable. For patients who were followed to day 180, seven of eight were stable or improved, and at day 270, three of three patients were stable or improved.Ontaneda also presented early CSF biomarker data. Median neurofilament light chain fell from 2900 to 2500 pg/mL by day 10, and 17 of 22 patients had an unchanged or reduced number of oligoclonal bands.In addition to continuing the current study and pushing up the enrollment numbers, researchers plan to assess higher doses and include individuals with relapsing forms of MS in future iterations of the study, said Ontaneda.“If this medication is safe and we see clinical benefit, we will move beyond phase one studies.”Cautious OptimismFor now, the safety results are the main takeaway from the study, said Jaume Sastre-Garriga, MD, PhD, neurologist at MS Centre of Catalonia in Barcelona, Spain, and editor-in-chief of the Multiple Sclerosis Journal, who was not involved in the research.“From the point of view of safety, it looks like there weren’t any major issues,” which is important because some studies have shown “significant toxicity” with CAR T-cell therapies that can be very serious, he said.An off-the-shelf product also simplifies treatment and “widens the availability of the therapy across different populations and in different contexts and settings,” Sastre-Garriga added.“This is a very promising field, and we are all very enthused with this strategy that is working so well for other diseases, particularly in the field of oncology, and is now being evaluated in autoimmune diseases like MS.”Still, he cautioned that the small number of patients makes it impossible to determine efficacy at this point.The study was funded by TG Therapeutics, the manufacturer of the product. Ontaneda and Sastre-Garriga reported having no relevant conflicts of interest.