Treatment with mesenchymal stem cells (MSCs) has failed to significantly reduce inflammation in the brain of adults with multiple sclerosis (MS) in a phase 2 clinical trial. The into-the-vein treatment also failed to improve other clinical aspects of the condition.
The results were shared in a study titled “Safety, tolerability, and activity of mesenchymal stem cells versus placebo in multiple sclerosis (MESEMS): a phase 2, randomised, double-blind crossover trial,” published in the journal The Lancet Neurology.
Into-the-vein treatment with mesenchymal stem cells (MSCs) failed to significantly reduce brain inflammation or improve clinical conditions among adults with active multiple sclerosis (MS) in an international Phase 2 clinical trial, according to final study data.
The trial, which used magnetic resonance imaging (MRI) scans to assess the therapy’s efficacy, found the intravenous treatment was well-tolerated, but did not show any of the “demonstrated neuroprotective and ‘tissue healing’ properties [seen] in other studies,” the researchers said in a press release.
“We failed to show, at least on the measures of MRI, that [MSCs] were able to control inflammation,” Mark Freedman, MD, a professor of neurology at University of Ottawa, in Canada, who co-led the trial in Canada, said in an explanatory video.
While these findings suggest an absence of MSCs’ beneficial effects in this patient population, they contrast with those previously reported for a specific subpopulation of MSCs, delivered directly into the spinal canal, in active, progressive MS patients.
As such, “more research is needed,” Freedman said in the video, shared by the MS Society of Canada. The scientist added that “the mode of delivery, the numbers [of cells], how often to give them are all things that are hopeful for research in the future.”
MSCs, which are capable of maturing into many other cell types, are found in several parts of the body, including the bone marrow, skin, and fat tissue. With their strong immunosuppressive, anti-inflammatory, neuroprotective, and regenerative properties, MSCs are gaining increasing interest as a potential therapeutic approach for a number of conditions.
A transplant of MSCs typically involves collecting these cells from a patient, expanding their numbers in the lab, and infusing them back into the person’s bloodstream — known as an intravenous injection — or into the fluid surrounding the brain and spinal cord, in which case it’s called an intrathecal injection.
Early animal studies suggested that MSCs are able to promote neural and tissue repair, influence the immune response, and lessen MS-like disease.
The MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) Phase 2 clinical trial evaluated the safety, tolerability, and effectiveness of bone marrow-derived MSCs in 144 adults with active relapsing-remitting MS or progressive MS.
Active MS was defined by recent relapses and/or evidence of MRI activity.
The participants, enrolled at 15 sites across nine countries, were randomly assigned to first receive either an intravenous injection of MSCs, followed by a later placebo injection (69 patients), or an initial placebo injection and, later, MSCs (75 patients). In both cases, the second injection was given at week 24, or about six months after the first.
The trial’s main goals were to assess the therapy’s safety and changes in the number of gadolinium-enhancing brain lesions, which reflect regions with active inflammation, at 24 weeks.
Secondary goals included changes in other MRI-based outcomes, number of relapses, and disability progression — as assessed with the expanded disability status scale (EDSS) — between the study’s start and 24 weeks, and then again between 24 and 48 weeks (about one year).
The mean age of the patients was 39, and 65% of them had relapsing-remitting MS. Of the rest, 23% had secondary progressive MS, and 12% had primary progressive disease.
The results showed that the one-year trial failed to meet all efficacy goals, with no statistically significant trends favoring MSCs over the placebo.
Notably, during the first six months, the mean annualized relapse rate (AAR) was nearly twice as high among patients initially assigned to the placebo relative to those given MSCs (1.1 vs. 0.6), but this difference did not reach statistical significance.
MSC treatment was generally safe and well-tolerated, with similar rates of adverse events between the groups in the first six months (about 53%), and between 24 and 48 weeks, or the second six months (59%).
The most frequently reported adverse events over the entire study were infections and infestations. Serious adverse events were reported in up to 8% of patients, and all were deemed unrelated to MSCs. No patient died during the study.
While MSC treatment “has been shown to be safe, regardless of the administration route,” neither inflammatory brain lesions on MRIs nor clinical surrogate markers of efficacy “in previous studies and in MESEMS” have shown effectiveness, according to the researchers.
“It’s important to recognize that there’s a lot of hype around these cells and that a lot of centers are making money on luring patients and promising them the opportunity to benefit from mesenchymal stem cells transplantation,” Freedman said.
“A lot of caution needs to be given to going to these centers since it was very difficult to prove, even in a very well-done trial, that the benefit is that easy to see,” he said.
Freedman and the other scientists from this Phase 2 study said more research is needed to determine if MSCs can in fact reduce disease worsening.
“Whether these negative results are attributable to a true absence of therapeutic activity of MSCs in multiple sclerosis, to the [different MS types] of enrolled patients, or to technical and methodological flaws in the experimental approach is still uncertain,” the researchers said.
Given MSCs’ neuroprotective and reparative properties in preclinical models of MS and their reported ability to delay disease progression in active, progressive MS patients within a small Phase 2 trial (NCT02166021), future, larger studies should assess whether MSCs can repair tissue and whether it is a valuable option for progressive MS patients, the team noted.
Future trials should also test different routes of administration, sources of MSCs, doses, and treatment regimens, as all could “still establish whether MSCs might be an appropriate therapeutic option for people with multiple sclerosis in the future,” the researchers wrote.
MSCs are found in several areas of the body, such as skin, bone marrow and fat. They are capable of maturing into lots of different types of cell.
MSCs have been gaining interest due to their immunosuppressive, neuroprotective, anti-inflammatory and regenerative abilities as a possible therapy for a lot of conditions.
To treat a patient, cells are collected from them, and then the number of cells is increased in a laboratory. They are then infused back into the patient’s bloodstream, which it’s known as intravenous injection. If it is injected into the fluid around the brain and spinal cord, it’s known as intrathecal injection.
There have been animal studies which have suggested that MRCs may be able to promote tissue repair, change the immune response and lessen MS-like disease.
In this trial, magnetic resonance imaging (MRI) scans were used to see if the therapy had benefitted the patients. While the intravenous treatment was found to be well-tolerated by them, they didn’t find any of the “demonstrated neuroprotective and ‘tissue healing’ properties [seen] in other studies,” the researchers said.
More research is needed, as these results were in contrast to results from another trial which saw beneficial effects in patients who had the cells directly injected into the spinal canal.