West Palm Beach, Florida — In an interim analysis of an extension study, intrathecal injection of autologous bone marrow–derived mesenchymal stem cells (MSCs) has been associated with favorable effects on both symptoms and biomarkers in patients with progressive multiple sclerosis (MS), new data presented as a late breaker at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024 showed.
After at least 1 year of follow-up in 23 patients participating in the extension analysis, "there has been favorable effects on cognitive function, neurological functional tests, quality of life, and both of two major biomarkers linked to neurodegeneration," reported study investigator Dimitrios Karussis, MD, PhD, Chairman of the Multiple Sclerosis Center, Hadassah Hospital, Jerusalem, Israel.
Based on promising preclinical studies, the initial clinical study with MSCs was published in Brain in 2020. In that study, 48 participants were randomly assigned to receive an intrathecal injection of MSCs, an intravenous injection of MSCs, or a sham injection. The MSCs were collected from the bone marrow of each participant and cultured.
A second injection in the active treatment groups was administered at 6 months. At this time, those initially randomized to a sham injection received either an intrathecal or an intravenous (IV) injection of MSCs harvested from their bone marrow.
No Disease Activity at 1 Year
When evaluated at the end of 1 year, there was no evidence of disease activity in 58.6% of those receiving the two intrathecal injections of MSCs, 40.6% of those receiving two IV injections of MSCs, and 9.7% of those initially randomized to the sham group.
The intrathecal injection of MSCs, which was well-tolerated, appeared to offer greater efficacy and was associated with relative benefits on multiple additional measures, including reduced T2 lesion load, lower relapse rates, and sustained cognitive function.
A total of 40 patients from the initial study were enrolled in the extension. In his presentation, Karussis provided interim results on 23, all of whom had been followed for at least an additional year. These patients were treated with one to three intrathecal injects of MSCs at intervals of 3-6 months.
Of further gains during the extension, Karussis described gains in cognitive function, represented by a three-degree improvement in the Symbol Digit Modalities Test, a median 17% improvement in the 25-foot walk test, and an improvement in quality of life, captured in domains of both physical and mental function. All of these gains were statistically significant.
The clinical responses were supported by reductions in both serum neurofilament light chain (sNfL) levels and in the glial fibrillary acid protein (GFAP), which Karussis described as important biomarkers of disease progression. For sNfL, the reduction was 33.2% (P = .001), and there was further decline observed after repeated MSC injections.
The 22% (P < .0004) reduction in GFAP, which Karussis said has not been shown before, was observed in all 23 patients. Again, there was an additional reduction with repeated MSC treatments. The therapy's safety and tolerability remained encouraging at longer follow-up.
As in the original series, there were no serious adverse events. Headache and backache, which were more common among those receiving intrathecal injections of MSC in the original study, continued to be reported in the extension, but these were time limited.
Although Karussis noted these interim results await confirmation with longer follow-up and larger studies, he suggested that the consistency of benefit with early report provides "an additional hint of possible neuroprotective and neurotrophic effects."
Too Early to Determine Utility
In patients with progressive MS, there is an urgent need for more and better therapies. MSCs, which reside primarily in bone marrow but can be found in other tissues, have been associated with immunomodulatory as well as neuroprotective effects in experimental studies, but whether one or the other or both of these activities are responsible for the clinical benefits observed so far are unresolved.
Others evaluating MSCs in the experimental setting have shown that these "produce a variety of soluble factors with immunomodulatory, neuroprotective, and repair-promoting properties," said Jeffrey A. Cohen, MD, who was asked to comment on the findings.
Cohen is director of the Experimental Therapeutics Program at the Mellen MS Center, Cleveland Clinic, Cleveland, Ohio. He said previous experimental work has encouraged clinical studies, including the work presented by Karussis.
While the presentation provided data suggesting "persistent potent efficacy with good safety and tolerability," Cohen noted that "the results from this group are substantially better than those reported by several other groups." He called the difference in results "uncertain," suggesting more work is needed to prove that clinical benefit is reliably achieved.
"I think it is too early to tell if MSC transplantation is going to be useful. Other than [the data] reported by the Karussis group, the results have been rather disappointing," Cohen said.
Karussis reported no potential conflicts of interest.