Stem cells for relapsing MS? They are safe, but they don’t work…Back to the drawing board

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You have been clamouring for stem cell therapy and the academics have done much to do such studies. There are still a number in the pipeline.

Sad to say this multi-national one is a bust and it did not meet its efficacy end-point targets, so simply put they did not work. The study was a safety study and I guess oen can make the point that it is a safe approach. However, giving people with MS tooth paste is safe. It does not say that tooth paste is going to affect MS.

However, these days it is easy enough to show a positive immune effect on relapsing MS and this failed. I know this is disappointing, but the pre-clinical animal data supporting an immune effect was really, really, really weak. So do not, and I mean do not blame the animals for this one…this is firmly in the hands of humans.

The community provided pressure on the academics to do these trials. The conclusions are we should more repair studies, but why do placebo trial in relapsing MS and not repair studies, where there is a clinical need? A failed trial is a black mark and reduces enthusiasm to do more studies

Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial.Uccelli A, Laroni A, Ali R, Battaglia MA, Blinkenberg M, Brundin L, Clanet M, Fernandez O, Marriot J, Muraro P, Nabavi SM, Oliveri RS, Radue E, Ramo Tello C, Schiavetti I, Sellner J, Sorensen PS, Sormani MP, Wuerfel JT, Freedman MS; MESEMS investigators.Lancet Neurol. 2021 Nov;20(11):917-929. doi: 10.1016/S1474-4422(21)00301-X.

Background: Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, have been proposed as a promising therapeutic option for people with multiple sclerosis on the basis of their immunomodulatory and neuroprotective properties. The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study was devised to evaluate the safety, tolerability, and activity of autologous MSCs derived from bone marrow and infused intravenously in patients with active multiple sclerosis.

Methods: MESEMS is a randomised phase 2 trial done at 15 sites in nine countries. Patients (aged 18-50 years) with active relapsing-remitting or progressive multiple sclerosis were included if they had a disease duration of 2-15 years since onset of multiple sclerosis and an Expanded Disability Status Scale score of 2·5-6·5. Patients were randomly assigned (1:1), according to a crossover design, to receive a single intravenous dose of autologous bone marrow-derived MSCs followed by placebo at week 24, or to receive placebo followed by autologous MSCs at week 24, with a follow-up visit at week 48.

Primary objectives were to test safety and activity of MSC treatment. The primary safety endpoint was to assess the number and severity of adverse events within each treatment arm. The primary efficacy endpoint was the number of gadolinium-enhancing lesions (GELs) counted over week 4, 12, and 24 compared between treatment groups. The primary efficacy endpoint was assessed in the full analyis set, after all participants completed the week 24 visit. Efficacy endpoints were evaluated using a predefined statistical testing procedure. Safety was monitored throughout the study by recording vital signs and adverse events at each visit.

Findings: From July 16, 2012, until July 31, 2019, 144 patients were randomly assigned to first receive early intravenous infusion of autologous bone marrow-derived MSCs (n=69) or placebo (n=75). MSC treatment did not meet the primary endpoint of efficacy on the total number of GELs accumulated from baseline to week 24 (rate ratio [RR] 0·94, 95% CI 0·58-1·50; p=0·78). 213 adverse events were recorded, similarly distributed between groups (93 cases recorded in 35 [51%] of 69 patients treated first with MSCs vs 120 cases in 42 [56%] of 75 patients infused first with placebo). The most frequent adverse events reported were infection and infestations, with a total of 54 (25%) of 213 adverse events (18 [19%] of 93 in the early-MSC group and 36 [30%] of 120 in the delayed-MSC group). Nine serious adverse events were reported in seven patients treated with placebo versus none in the MSC group. All serious adverse events were considered to be unrelated to the treatment infusion. No deaths were reported during the study.

Interpretation: Bone marrow-derived MSC treatment was safe and well tolerated but did not show an effect on GELs, an MRI surrogate marker of acute inflammation, in patients with active forms of multiple sclerosis, at week 24. Thus, this study does not support the use of bone marrow-derived MSCs to treat active multiple sclerosis. Further studies should address the effect of MSCs on parameters related to tissue repair.

Before you start bombarding me with stories about other stem cell studies. We have got over twenty different inhibitors of relapsing MS and it is clear that these cells are not good enough for this indication.

COI We were part of this initiative. There is another story to tell

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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MouseDoctor

15 comments

  • It’s simple physics. Law of entropy means everything eventually moves to disorder ie even a stable particle like proton will become radiation. To repair requires input of energy and create a ordered state. If the destruction process 9f the immune is not switched off, even if stem cells are working there will be negligible effect. I guess som academics are only in name

    • “MSC big scam everywhere?”

      Yes…..Horrible to see go fund me looking to raise $20,000
      for MSC stem cells + $2,000 in vitamins/supplements.
      We are probably 50-100-200 years from being able to restore
      CNS tissue in brain and spine.

      Dr. Burt said once he was working with MSC…”Behind the Curtain”
      but since he made no further announcements…assume no/poor results

    • MSC is not even real stemcell, it may have minimal influences on immune even if there is it wouldn’t be comparable to current DMTs – but hey, at least it has no known side effects!

      • Do you think neural stem cells are different…these too have been touted as immunomodulators based on EAE data just like MSC and in my opinion are just about as good…or should I say bad as an immune modulator.

  • I’d like to see a study that noted what medication for MS the people were on, as I expected this to be an add on treatment, like a ketogenic diet, for symptom improvement. Is 9 serious events in the placebo group curious?

  • In some trials that show positive results, alot of the time you will say the trial design wasn’t great

    Also the same for this, if somethings expected to do well, the trail design may not be great

    Could the same be said about this??

    Also what would the mechanism of action be of MSC reducing immune activity in the CNS, I can’t see the connection there

      • I dint mean MSC specifically, I ment in general in this blog, trail designs are usually highlighted as being an issue for poor results or positive results

        Sound like trail designs in the medical profession need reviewing as there are lots of inaccuracies and conflicts of interest etc.

        Could this also be the case for this trial, however where it the connection between MSC and immune regulation, I just can’t see it. MSC are more the building blocks of the body that differentiate.

        Inflammation surely is the wrong target for MSCs ?

        • Where is the connect MSC and inflamation…three letters and that is EAE.
          Next issue is trial design by numbers…and trials are done the same way over and over again…but that is to be suspected as you have a limited number of academic neurologists on the advisiory boards…Few people are willing to stand up to the big swingers to question their authoritee

  • COI We were part of this initiative. There is another story to tell

    You can’t tease us and then not tell us the other story? Can you give us any info re the other story as I am very curious about this treatment? Thanks!

    • “COI We were part of this initiative. There is another story to tell”

      Most likely they were consulted..they advised them this is wrong cause of XYZ…
      and they didn’t listen.

  • I am confused MD. Why is this trial looking only at inflammation when mesenchymal stem cells are also supposed to be mainly reparative in nature? If they are looking for remyelination or neuro-restoration, why is the trial just seems to be looking at gadolinium enhancing lesions on MRI as the endpoint? Shouldn’t the focus be on other measures that actually measure remyelination or neuro-restoration, like optic nerve CT thickness, visual evoked potentials and clinical performance outcomes. I also do not understand patient selection. Why do the patients in this study need only “active” MS if they are looking at reparative process? Seems that all they have answered is that mesenchymal stem cells are not a good anti-inflammatory and not whether it is reparative or not? I must be missing something.

  • It’s strange that their primary outcome was lesions… I thought we already solved lesion formation and mesenchymal stem cells are about attempting repair.

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