Mostly discouraging trial of MSC-NPs or purported neural cells from MSCs for MS

The idea of mesenchymal cells or MSCs for MS has been around for a long time. However, there haven’t been that many strong clinical trials testing it. There’s a new paper out that reports one of the stronger MSC-related trials for MS in terms of design. In this case, they didn’t use just MSCs but reported deriving a “neural progenitor” population from the MSCs. They call these cells MSC-NPs.

How’d it turn out?

The main takeaway is that this is a discouraging trial but they say that some patients may have benefited. Overall, there are some interesting elements to this including the idea of MSC-NPs.

Let’s do a quick journal club-type review of this paper.

Journal club review of MSCs for MS trial paper: overview

The new paper is entitled Efficacy of intrathecal mesenchymal stem cell-neural progenitor therapy in progressive MS: results from a phase II, randomized, placebo-controlled clinical trial. It’s in the journal Stem Cell Research and Therapy and comes from a team at the Tisch MS Research Center of New York.

As I noted, this trial was designed to be stronger than many others in this space. Here’s its description: “investigator-initiated, phase II, double-blind, placebo-controlled, randomized, parallel group clinical trial with a compassionate crossover design.”

It’s worth noting for context that if you believe that MSCs can benefit MS or other CNS conditions, to me it makes much more sense to do intrathecal administration (as they did here) rather than systemic delivery. I just don’t see how an IV of MSCs is going to lead to lasting benefits for any of the many diseases it is marketed for by unproven clinics including MS. Even if it worked, people would need repeated infusions. On the other hand, intrathecal MSCs likely pose more risks, but this and other studies have reported solid safety profiles.

MSCs for MS trial fails to meet primary endpoint

The disappointment here is that this trial failed to meet its endpoints. As with some other clinical trial reports on cell therapies, this one then goes into post-hoc, subgroup analysis. I’m not very convinced about the claims related to the post-hoc analyses in the paper.

Further, more generally I haven’t seen such post-hoc analyses be predictive of efficacy in follow-up cell therapy trials that initially failed to meet their primary endpoints.

I was initially encouraged by their bladder function data showing possible improvement with the cells but then realized it was only done with data from some placebo and some MSC-treated participants. People with more normal bladder function were also excluded entirely. The hope is that there was some real benefit in bladder function, but we can’t be sure. Is another trial warranted following up on this? The team also report a reduced rate of grey matter atrophy on brain MRI in some patients given MSC-NPs.

Why would only some MS patients benefit from MSCs?

Another interesting element in this study is that patients who were worse off in terms of walking ability (high EDSS) reportedly had more potential for benefit from cells. I’m not sure why that would be.

This also raises a larger question: why might only some people in a trial benefit from MSCs? It’s not always clear. Sometimes it’s the people who are worse off to start but it can also be vice versa. You can make the argument that MS patients with less severe disease may be more receptive to cell therapy. Maybe there’s less inflammation and so perhaps better survival and eventual engraftment? As a side note, we don’t know in this intrathecal study if any of the MSCs engrafted.  Even without engraftment, MSCs could have positive trophic effects, but they’d most likely be transient.

But why would patients who are worse off benefit more? They have more opportunity for gain?

What are MSC-NPs and do they have neuronal cell properties?

Then there is the issue of what exactly were the cells used here. The authors state that the cells are neural progenitors derived from bone marrow MSCs or MSC-NPs, but is that even possible? I thought there was a consensus from the literature is that MSCs do not have neural potential. I also just bounced this off of two scholars in the field and they concur with that. Also, why would bone marrow have cells with neural potential?

So what are the MSC-NPs in this study? I’m not sure. Could this particular MSC culture somehow contain isolated neural progenitors (or cells that could become neural progenitors)  along with MSCs from marrow? Then the team derived just the neural progenitors from that mixed population? I wonder if the MSC-NPs can differentiate into neurons and/or glia? Oligodendrocytes? An earlier paper reports that such differentiation can be observed.

From that study, we also get more derivation details:

” For MSC-NPs, MSCs were cultured in low-adherence flasks in serum-free neural progenitor maintenance medium (NPMM) (Lonza) containing 20 ng/ml each of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) for 21 days with a medium change every 2–3 days. Floating “neurospheres” were visible after 2–5 days.”

This is a fairly standard neurosphere protocol. They also have shown some lineage marker staining. I’m still not convinced that there are neural progenitor-type cells in marrow MSC cultures.

Looking ahead

Why did the study fail to meet its primary endpoint? The authors write:

“The study did not meet the primary efficacy endpoint of a positive change in EDSS Plus when comparing MSC-NP and saline groups due to a large unanticipated placebo effect.”

I’m not sure one can say this placebo effect is the sole reason it didn’t meet the endpoint but it is interesting that there might be such a strong placebo effect at times. If there was a big placebo effect here, then could some of that have come from participants being excited about the idea of getting “stem cells” and then some of them just get placebo but some part of them thought they got the cells?

The other possible reason for not meeting the primary endpoint is that the cells just don’t work in the hoped-for way.

In the big picture, when it comes to cell therapies or specifically stem cells for MS, I’m relatively more excited about the HSCT approach with HSCs after partial ablation by chemo, which seems to yield strong benefits for many MS patients with certain types of disease. The trials in that area have been more compelling.

I’ll be curious to continue to follow this MSC-NP line of research too.

References

• The National MS Society has a solid info page on stem and other cells including MSCs for MS. I don’t think they are quite skeptical enough there, but it’s a helpful collection of summaries of trials in this space.
• I also included a video above of senior author Saud Sadiq on an earlier trial of MSC-NPs for MS.