by Richard Robinson
BOSTON—Intravenous infusion of autologous stem cells is safe in multiple sclerosis (MS), according to final results from a recently completed trial. But the single dose used in the trial provided no evidence of effectiveness. Another trial just getting underway suggests that intrathecal administration is also safe, but the question of whether multiple doses can help repair a damaged nervous system may remain even once the final trial results are known.
The cells used in both trials were mesenchymal stem cells (MSCs), derived from patient bone marrow and then purified and expanded in vitro.
“One of the reasons there has been such an interest in mesenchymal stem cells is that there are established methods to confirm purity and functional capacity,” said Jeffrey A. Cohen, MD, who led the intravenous trial. Dr. Cohen, director of the experimental therapeutics program at the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic, presented the findings in September at the joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
A bone marrow harvest in progress. Image via Wikimedia Commons.
Results from the experimental autoimmune encephalitis (EAE) mouse model of MS provided the rationale for the therapy, showing that injected cells can migrate to the site of inflammation and aid in remyelination.
Dr. Cohen led a study in which 24 MS patients received a single intravenous infusion of 1-2 million cryopreserved autologous MSCs. Patients were followed for the two months it took for the withdrawn cells to be expanded, and then for six months after treatment. The last patient completed follow-up in January 2014.
Feasibility and safety were the primary outcomes for the Phase I trial. “Overall, we encountered no significant safety issues,” he said. “There were, in fact, very few if any side effects, and certainly no serious or severe adverse events.”
There was no indication of any increase in lesions, “but also no apparent benefit,” Dr. Cohen said. The researchers observed no change in either median or mean disability scores, although a few patients showed some improvement. “While there was no evidence of disease activation, there was also no evidence of benefit on any of these measures for patients as a group,” he said.
The results of the study “support the feasibility, safety, and tolerability” of intravenously administered MSCs for MS, Dr. Cohen said. But “there are a number of issues that need to be resolved before moving to Phase II [trials],” including dose, number of treatments, whether cells from a disease-free donor might offer advantages, and whether cells should be cryopreserved, as they were in this study, or injected fresh from the expansion culture.
Meanwhile, Saud A. Sadiq, MD, FAAN, director of the Tisch MS Research Center of New York, is leading an ongoing study of infusion of autologous MSCs, which differs in several potentially important ways from Dr. Cohen’s study. The stem cells in his study are infused intrathecally, they are fresh — not cryopreserved — and patients receive three doses, not one. In addition, the MSCs are treated during the expansion process with growth factors to convert them to neural progenitor cells. “This reduces their lipidogenic and osteogenic potential, which had been thought to be a risk,” Dr. Sadiq explained.
The multiple dosing was based on preclinical work in the EAE mouse. “We found that a single dose had very little effect while multiple doses led to a sustained clinical benefit,” with improvement in the EAE clinical score and a decrease in demyelination and T-cell infiltration, he noted.
An unpublished initial clinical study in six patients, some of whom are now in their ninth year of follow-up, suggested the treatment was safe, with no formation of tumors or ectopic tissue.
That led to the current trial, in which 20 patients will receive three injections of up to 10 million cells each, spaced three months apart. So far, three patients have received at least one infusion; one patient had received two infusions at the time of the presentation. Dr. Sadiq said that so far there have been no adverse effects, except for spinal headache.
“We think that if there are any benefits, it is probably based on the growth factors that the cells secrete, the local immunoregulatory effects they would have, and migration to sites of injury,” Dr. Sadiq said. “We don’t think there is a direct remyelination by these cells.”
Dr. Cohen concurred. “We don’t think these cells directly replace cells in the nervous system,” he said. “If they promote repair, it is by enhancing intrinsic repair mechanisms.”
Look for the full discussion and more news from the ACTRIMS/ECTRIMS joint meeting in the Nov. 6 issue of Neurology Today. For more coverage of MS research, browse our archives here: http://bit.ly/NT-MS.
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