The 2026 annual ACTRIMS Forum convened in San Diego under the theme “At a Crossroads,” an apt description for a field in which conventional immunomodulation is rapidly evolving to more precise, cellular-based interventions. Among the most closely watched developments this year was the emergence of CAR-T therapy as a plausible disease-modifying strategy for progressive forms of MS. Data presented in two complementary posters from the Stanford group provided an early but compelling glimpse into how this technology may reshape the therapeutic landscape.
For decades, MS treatment has focused primarily on controlling peripheral immune activity through broad immunosuppression or selective B-cell depletion. While these approaches have dramatically reduced inflammatory relapses, they have been less effective in progressive phenotypes, where smoldering compartmentalized inflammation and neurodegeneration have been implicated in disease progression independent of relapse activity (PIRA). CAR-T therapy offers a fundamentally different approach: the creation of a living drug capable of trafficking into immune sanctuaries, including the central nervous system, recognizing pathogenic cell populations, and recalibrating immune networks from within.
A first-in-human Phase 1 trial of KYV-101, an autologous fully-human anti-CD19 CAR-T product, represented one of the first systematic attempts to apply this strategy to progressive MS. As detailed in the clinical outcomes poster, six participants with either secondary or primary progressive disease underwent leukapheresis, CAR-T manufacturing, and reinfusion following lymphodepleting chemotherapy with bendamustine (given at 90 mg/m2 IV days 5 and 4 before autologous CAR-T infusion). To optimize safety, the trial was structured in a 3 X 3 dose-ranging design in which subjects 1-3 received 33 million CART cells, and subjects 4-6 received 100 million cells.
The investigators demonstrated robust expansion of both CD4 and CD8 CAR-T populations in the peripheral blood, with peak proliferation generally occurring between days 5 and 21. Importantly, CAR-T cells were also detected in cerebrospinal fluid by CAR-FACS assay by Day 14 in all subjects, providing direct evidence that engineered lymphocytes can access the central nervous system, a critical prerequisite for addressing compartmentalized neuroinflammation.
Safety outcomes were encouraging. Although cytokine release syndrome (CRS) occurred in several participants, all cases were mild to moderate and manageable with standard interventions such as dexamethasone or tocilizumab. No severe neurotoxicity was observed. These findings are particularly noteworthy given the vulnerable, chronically disabled population being treated and the well-known toxicities of CAR-T therapy in oncology.
Evidence of biological activity extended beyond simple cell kinetics. Serum immunoglobulin levels fell modestly, but protective antibody titers to diphtheria, tetanus, and Epstein–Barr virus (EBV) were largely retained. A profound depletion of circulating CD19+ B cells was achieved in all participants, with B-cell reconstitution observed in all subjects by three months. The reconstituted B cells exhibited a canonical naïve B cell phenotype, indicating that baseline CD27+ memory B cells had been eliminated both peripherally and intrathecally in CAR-T-treated subjects. This latter point is especially relevant to MS pathogenesis: EBV-infected memory B cells are regarded as potential drivers of disease. Their accretion into CNS meningeal B cell follicles has been associated with progressive MS phenotypes. The ability of CAR-T cells to lyse these reservoirs raises the provocative possibility of a true immune reset, targeting one of the fundamental etiologic substrates of MS rather than merely its downstream inflammation.
Clinical signals, while preliminary, were similarly intriguing. The poster reported stabilization or modest improvement across several disease-specific metrics, including EDSS scores, patient-reported outcomes, and quality-of-life measures. Given the inexorable decline typically expected in progressive MS, even hints of functional benefit warrant attention.
The immune effects of CAR-T therapy were demonstrated in part by Timmons and colleagues. Using multiplex Luminex assays, investigators tracked 115 immune analytes across multiple time points. A clear temporal pattern emerged: soon after infusion, there was a coordinated surge in pro-inflammatory mediators, including TNF-α, IFN-γ, and IL-6, paralleling the period of maximal CAR-T expansion. This predictable inflammatory wave mirrors observations in oncology and likely reflects on-target immune activation as CAR-T cells encounter and eliminate B cells. Importantly, this early immune activation was shown to be transient. By day 28, concentrations of many cytokines implicated in MS pathophysiology, such as IL-12p70, IL-17F, GM-CSF, TNF-α, and IFN-γ, had returned to or fallen below baseline levels. Chemokines involved in immune cell trafficking, such as CCL2, CXCL9, and CXCL10, showed similar normalization. The investigators interpreted this as evidence that CAR-T therapy may induce a durable recalibration of the immune milieu rather than simply imposing temporary suppression.
A dose-response signal was also observed. Participants receiving the higher cell dose (100 million versus 33 million) displayed more pronounced cytokine elevations, suggesting that the intensity of immune remodeling may be titratable. Such insights will be foundational for designing subsequent trials that balance efficacy with tolerability.
Taken together, these posters portray CAR-T therapy as more than an incremental addition to the MS armamentarium. The technology uniquely addresses several longstanding challenges in the field. It provides a means to penetrate the central nervous system, to eradicate pathogenic memory B-cell niches harboring latent EBV, and to reset dysregulated cytokine networks that drive chronic inflammation. Unlike monoclonal antibodies, CAR-T cells access the CNS and B cell sanctuary sites, and offer the possibility of a durable, perhaps even one-time, treatment.
Many questions remain. The durability of clinical benefit, the optimal dosing strategy, and the long-term consequences of sustained B-cell aplasia will require careful study. Larger, controlled trials are needed to determine whether the immunologic shifts observed here translate into meaningful slowing of disability progression.
Yet the significance of these early findings should not be understated. At a moment when the MS field truly stands at a crossroads, the 2026 ACTRIMS data presented by the Stanford Neuroimmunology team suggest that cellular immunotherapy may offer a new path forward, one that moves beyond modulation toward immune re-engineering. If future studies confirm these initial signals, CAR-T therapy could mark the beginning of a transformative era for patients with progressive MS, who have long awaited genuinely innovative and more efficacious treatment options.
Dr. Dunn has received research support from Kyverna, and consulting fees from Genentech and Sanofi.
Image by DrAfter123 / Getty Images
