NeuroVoices: Jeffrey Cohen, MD, on Stem Cell Strategies and the Future of Multiple Sclerosis Therapeutics

Over the past two decades, the therapeutic landscape in multiple sclerosis has transformed dramatically, with more than 20 disease-modifying therapies now available to clinicians. High-efficacy monoclonal antibodies and immune-depleting strategies have meaningfully reduced relapse rates and inflammatory MRI activity for many patients. Yet, despite this progress, a subset of individuals with relapsing MS continues to experience breakthrough disease or incomplete disease control. For these patients, immune reconstitution strategies, including hematopoietic stem cell transplantation (HSCT), have emerged as a potential alternative approach aimed at fundamentally resetting immune function.

HSCT has accumulated a growing body of observational and clinical trial data demonstrating durable suppression of inflammatory activity, in some cases lasting 5 to 15 years without the need to resume disease-modifying therapy. However, questions remain regarding patient selection, comparative effectiveness against modern high-efficacy therapies, procedural risk, and standardization of transplant protocols. In parallel, the field has expanded to include additional cell-based strategies, including CAR T-cell therapies, as well as regenerative approaches targeting remyelination and repair. Determining how these evolving modalities fit into the broader MS treatment paradigm remains an active area of investigation.

At the 2026 ACTRIMS Forum, held February 5-7 in San Diego, California, Jeffrey Cohen, MD, director of the Clinical Neuroimmunology Fellowship and professor of neurology at Cleveland Clinic, delivered the Kenneth P. Johnson Memorial Lecture, focusing on stem cell–based strategies in MS. As part of a new iteration of NeuroVoices, Cohen provided background on HSCT, discussed ongoing randomized trials such as BEAT-MS, examined the challenges of repair-focused studies, and shared his broader reflections on where cellular therapies may reshape the future of MS care.

NeurologyLive: For clinicians who were unable to attend your presentation, can you provide some background on what you discussed and why this topic remains important?

Jeffrey Cohen, MD: Kenneth B. Johnson was one of the pioneers in developing disease-modifying therapies for MS, and he was very supportive of me early in my career. I was honored to give a lecture in his name.

My talk focused primarily on hematopoietic stem cell transplantation. Despite the fact that we now have more than 20 disease-modifying therapies with regulatory approval for MS, there are still individuals who do not achieve complete disease control with available treatments. In that situation, hematopoietic stem cell transplantation has been considered as an alternative strategy.

There is now a fairly sizable literature on transplant in MS demonstrating very potent efficacy that appears durable. In some series, patients remain free of inflammatory disease activity for 5, 10, or even 15 years without restarting disease-modifying therapy. That durability is one of the most compelling aspects of the approach.

However, the literature also has shortcomings. Many studies are observational, patient populations vary, conditioning regimens differ across institutions, and comparisons against modern high-efficacy therapies are limited. To address these gaps, several ongoing randomized multicenter trials are underway. One of these is the BEAT-MS trial, for which I serve as lead investigator. In my presentation, I summarized the design of BEAT-MS and provided an update on its progress.

Another important issue is that there is still uncertainty about the optimal transplant protocol. Different centers use different conditioning regimens and approaches. For autoimmune diseases such as MS, we need greater clarity regarding what protocol maximizes benefit while minimizing risk.

Can you provide more insight into the clinical trials currently underway and where the broader cell therapy pipeline stands?

There are several different cell-based approaches being explored in autoimmune diseases like MS. Hematopoietic stem cell transplantation is the most advanced. The rationale is as an anti-inflammatory strategy. The immune system is eliminated using high-dose chemotherapy, referred to as the conditioning regimen, and then hematopoietic stem cells are reinfused to regenerate the immune system. The goal is to reform the immune repertoire so that it functions more normally and no longer drives autoimmune inflammation.

The ongoing randomized trials are enrolling patients with relapsing MS who continue to have disease activity despite treatment but who have, at most, moderate disability. That patient profile appears to be most likely to benefit from transplant and least likely to experience harm. Although the trials differ somewhat in details, collectively they should provide important information about how transplantation compares with currently approved high-efficacy medications.

In addition to HSCT, there are other anti-inflammatory cell-based strategies under investigation. CAR T-cell therapies are among the most notable. These are engineered T lymphocytes designed to recognize a specific target and eliminate it. In MS, the target is typically B cells. The concept is similar to B-cell–depleting monoclonal antibodies, but the theoretical advantage of CAR T cells is that they may deplete B cells not only in the peripheral blood but also in tissues, potentially including the central nervous system. That could result in deeper and more durable depletion.

There are now a sizable number of CAR T-cell trials underway. It is still relatively early, but the preliminary data are promising.

Beyond immune depletion, there is another broad category of stem cell strategies aimed at repair. This remains an area of major unmet need in MS. Mesenchymal stem cell trials were conducted with the goal of supporting endogenous repair mechanisms within the nervous system. The results have been mixed. Some signals were encouraging, but overall the magnitude of benefit has been limited, and it remains unclear whether this approach will ultimately prove effective.

There have also been pharmacologic strategies targeting remyelination. Agents such as anti-LINGO antibodies and clemastine have shown some evidence of remyelination in clinical trials. However, the effect sizes have been relatively modest. Repair remains an important objective, but it has proven to be biologically complex and challenging.

From a trial design perspective, what considerations are most important when building these studies?

Trial design is critical. For repair-focused strategies, the limited success to date may reflect multiple factors. It could be that the agents tested were not sufficiently potent. It could also be that trial design was suboptimal in terms of patient selection, endpoints, or duration. Alternatively, there may be more fundamental biological constraints on the capacity of the human central nervous system to repair itself.

For pivotal phase 3 trials, I believe traditional disability measures are appropriate. If a therapy produces meaningful restoration of function, established clinical outcomes should detect that effect.

The greater challenge is at the phase 2 proof-of-concept level. Historically, brain atrophy was thought to be a useful intermediate outcome for neuroprotective or repair strategies. However, we have learned that brain atrophy measurements have limitations, including variability and confounding factors.

Measuring remyelination in small phase 2 trials is particularly challenging. We do not yet have optimal biomarkers or imaging techniques that are sensitive and specific enough to confidently detect remyelination in short-term studies. This is an area where methodological improvements are needed.

Do endpoints need to evolve for cell-based and repair trials?

For large phase 3 trials, traditional disability endpoints remain appropriate. If a therapy truly restores neurological function, that should be measurable.

However, at the phase 2 level, we lack sufficiently sensitive tools. Our current measures may not be ideal for detecting subtle or early repair effects. That creates uncertainty when interpreting modest results. It can be difficult to determine whether a therapy failed biologically or whether we failed to measure its effect properly.

Developing better phase 2 outcome measures, particularly for remyelination and neuroprotection, is an important priority for the field.

What were your broader reflections from the 2026 ACTRIMS Forum?

The ACTRIMS Forum has always emphasized two core principles. First, it uses a single-track format organized around a specific theme. That allows for a coherent, nonredundant program where attendees are not forced to choose between parallel sessions.

Second, the Forum prioritizes opportunities for early-career investigators and trainees to present and engage with senior faculty.

Both principles were clearly evident this year. The thematic structure was effective, and the scientific quality was consistently strong. Young investigators played an increasingly prominent role. I think the format has been very successful, and while incremental improvements occur each year, I do not anticipate major structural changes.

Transcript was edited for clarity. Click here for more 2026 ACTRIMS Forum coverage.