The director of the Mellen Center for MS Treatment and Research at Cleveland Clinic discussed the realistic outlook of mesenchymal stem cells and other approaches to progressive MS.
Lead investigator Jeffrey Cohen, MD, and colleagues conducted a phase 2 study that evaluated the safety and efficacy of intrathecal administration of autologous mesenchymal stromal cells secreting neurotrophic factors (MSC-NTF) in patients with primary or secondary progressive multiple sclerosis (MS) across 4 US sites. Per protocol, participants received 100M-125M intrathecal MSC-NTF cells by lumbar puncture at weeks 0, 8, and 16, and then were followed to week 28.
At the conclusion of the trial period, 14% and 13% of participants showed at least 25% improvement in Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT). None of the 46 matched participants in the CLIMB registry, a comparison cohort, achieved these outcomes during comparable follow-up. Mean improvements of 10% in T25FW and 4.8% in 9HPT dominant hands were also observed for patients treated with MSC-NTF cells, compared to 1.8% and 1.4% worsening in CLIMB.
Cohen, director, Mellen Center for MS Treatment and Research, Cleveland Clinic, sat down with NeurologyLive for a new iteration of NeuroVoices to discuss the findings from the study, along with why MSC-NTF cells represent an intriguing approach to progressive MS. He also stressed the need to continue to try to break through the barriers of progressive MS, as it remains the most challenging form of MS to treat.
Jeffrey Cohen, MD: One of the big unmet needs in multiple sclerosis is treatments that promote repair, reverse damage, and improve neurologic function. One of the approaches that’s received a lot of attention had been transplantation of mesenchymal stem cells. There have been a number of previous preliminary studies. From those studies, we’ve learned that the cells need to be modified to augment their production of neurotrophic factors. That way they’re more efficacious. Secondly, we also learned that multiple administrations are probably needed. Thirdly, that intrathecal administration through spinal tap is probably more effective in this setting than intravenous injection. This phase 2 study incorporated those previous lessons to investigate whether one particular kind of mesenchymal stem cells, called MSC-NTF cells, could be administered by spinal tap safety, and whether there was some preliminary evidence of benefit.
Specifically, we have a number of disease-modifying therapies that primarily are effective in earlier stages of the disease, relapsing-remitting MS. Some of them have shown some benefit in progressive MS, but the benefits are modest, and primarily in people who are still having relapses or active MRI. Progressive MS represents a major unmet need in the field. We think that the therapies that are going to be effective will have different actions than our currently available therapies. They’ll have neuroprotective activity, or they will promote repair. Several aspects of mesenchymal stem cell function appear to meet those needs. They produce a wide range of neurotrophic factors that we think have both neuroprotective and repair-promoting properties.
Both are important. We knew from the outset that this was going to be a relatively small study. Our primary goal was to confirm feasibility of the procedures and safety, and then to get preliminary indications that the cells were biologically active. We focused to a great extent on biomarkers in the blood, but, in particular, in the spinal fluid, which was obtained at each of the cellular injections. Those studies showed quite promising results, with a decrease in the number of inflammatory biomarkers and an increase in the number of neuroprotective or neurotrophic biomarkers. Those studies were encouraging.
We also wanted to look in a preliminary way at some clinical end points, but we recognize that the study was small and open label, with no comparison group. One must interpret those results with a bit of caution. Those results were also encouraging, with approximately one-third of patients showing a clinically meaningful in several neurologic assessments. For more context, we compared the results in this study to a matched cohort from the Harvard CLIMB registry. That’s a registry of patients with MS that have been followed for a few years. We also compared it to the phase 2 SPRINT study of ibudilast. Those comparisons showed that a higher proportion of participants in our study showed improvement than what would be expected compared to those studies. Those results were preliminary but encouraging.
There have been quite a few studies of mesenchymal stem cells in MS. Most of them showed safety, but efficacy was rather inconsistent. We’ve learned a lot of important lessons from those studies. As I mentioned, we incorporated some of those lessons into this study. Once we start to get an initial indication of how to do this kind of study, the progress can be accelerated. What I expect is we’ll take what we learned from this study and incorporate it into a larger, more definitive trial, which we’re in the process of planning now. You’ll see the progress will start to come out at a faster rate in this area.
We’ll need treatments that prevent further worsening. Disease-modifying therapies for progressive MS will probably have to be different modes of action compared to our currently available therapy. One approach that seems very promising are the so-called BTK (Bruton tyrosine kinase) inhibitors. There have been a number of studies underway of those agents in progressive MS, but we will probably have to combine that with other approaches that repair damage that has already occurred. What I expect is that over the next few years, you’ll start to see new disease-modifying therapies under investigation, or a range of repair-promoting strategies with the ultimate goal that those could be combined.
There are a couple of ways in general to improve upon what we already have. One is to develop better, different treatments that work in a different way. The second is to optimize how we utilize what’s available. That’s the right treatment for the right patient. Thirdly, another alternative would be to combine the therapies we already have. We know that they work via different mechanisms, and we may get more bang for our buck by combining them. In particular, an immune mediated therapy combined with a repair-promoting strategy makes a lot of sense.
The biggest step that’s going to have a lot of pay-off in the future is the initial identification of biomarkers that can be used to monitor progressive MS. Fluid biomarkers such as neurofilament light, or GFAP. Both of those indicate damage to the central nervous system. Additionally, the identification of some MRI markers of progression. That’s the so-called phase dark rim lesions and slowly enlarging lesions. Both of those show promise as an indicator of ongoing damage in progressive MS. We need biomarkers, both fluid and imaging, to carry out preliminary studies in progressive MS. We’ve not had those until now.
Transcript edited for clarity.