An experimental donor-derived CAR T-cell therapy has shown no serious safety signals in an early study of people with progressive multiple sclerosis, offering an early indication that an \u201coff-the-shelf\u201d cellular therapy may be feasible in the disease.<\/p>\n
The therapy, azercabtagene zapreleucel, or azer-cel, is an allogeneic CD19-directed CAR T-cell treatment. Unlike conventional CAR T therapies, which are made from a patient\u2019s own cells, it uses cells from healthy donors that can be manufactured in advance and stored for use when needed.<\/p>\n
The phase 1 results were presented on 23 October at the 10th Joint ACTRIMS-ECTRIMS<\/a> meeting in Toronto. They come from a study of 26 adults with primary progressive, active secondary progressive or nonactive secondary progressive multiple sclerosis.<\/p>\n Early safety findings<\/strong><\/p>\n Among 18 patients with refractory progressive MS, treatment produced no dose-limiting toxicities, severe cytokine release syndrome, significant neurotoxicity or graft-versus-host disease. Two patients experienced low-grade cytokine release syndrome\u2014one grade 1 and one grade 2\u2014and two patients had grade 1 immune effector cell-associated neurotoxicity syndrome. Both groups recovered well, according to study investigator Daniel Ontaneda of Cleveland Clinic.<\/p>\n The study evaluated six doses. Its primary endpoint was dose-limiting toxicity associated with cell therapy, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, graft-versus-host disease and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. No dose-limiting toxicities or high-grade CAR T-associated toxicities were reported through day 28.<\/p>\n Eleven patients experienced treatment-emergent adverse events of grade 3 or higher, and four serious adverse events were reported. The researchers did not observe a consistent increase in adverse events at higher doses.<\/p>\n What the treatment did<\/strong><\/p>\n Treatment depleted B cells in the blood in 25 of 26 patients and showed an early signal of B-cell reduction in cerebrospinal fluid. As B cells returned, they were enriched for transitional and naive phenotypes, with fewer switched memory B cells.<\/p>\n The rationale is that existing anti-CD20 therapies control much of the inflammatory activity in MS, but some patients continue to accumulate disability. CAR T cells may reach parts of the central nervous system that are less accessible to peripherally administered antibodies and may produce a deeper effect on B cells.<\/p>\n Early clinical measures were encouraging but must be interpreted cautiously. At 90 days, disability scores remained stable or improved in all 18 evaluable patients. Three patients improved by two or more points on the Expanded Disability Status Scale<\/a>, including one with a four-point improvement.<\/p>\n Among patients followed to day 180, seven of eight were stable or improved; at day 270, all three patients followed to that point were stable or improved. Median neurofilament light chain, a marker associated with nerve damage, fell from 2,900 to 2,500 pg\/mL by day 10.<\/p>\n Promising, but not proof of benefit<\/strong><\/p>\n Independent expert Jaume Sastre-Garriga said the main takeaway is the safety signal. He noted that CAR T-cell therapies can cause significant toxicity, so the absence of major safety issues is important. He also said that an off-the-shelf product could simplify treatment and widen availability.<\/p>\n But he cautioned that the small number of patients makes it impossible to determine efficacy at this stage. The early clinical improvements cannot yet be attributed confidently to the therapy, and longer studies with more participants are needed.<\/p>\n Researchers plan to continue the study, enroll more participants, assess higher doses and eventually include people with relapsing forms of MS. If safety and clinical benefit are confirmed, the programme could move beyond phase 1 testing.<\/p>\n For now, the results represent an early proof of concept: a donor-derived CAR T-cell therapy can be administered in progressive MS without the serious toxicities seen in the initial safety assessment. Whether it can change the course of the disease remains an open question.<\/p>\n