Experimental cell-based strategies for MS progress to clinical trials against available disease-modifying therapies.
Jeffrey Cohen, MD
The recently published consensus report from the 2015 International Conference on Cell-Based Therapies for Multiple Sclerosis describes progress with several interventions, with the most extensively investigated, immunoablation followed by autologous hematopoietic stem cell transplantation (I/AHSCT), demonstrating efficacy in relapsing-remitting multiple sclerosis (MS).
With methodological and safety concerns associated with I/AHSCT and other cell-based interventions, however, the principle question posed by the conference is where their benefit-risk-cost profiles place them relative to the available and effective disease modifying therapies (DMTs).
Several cell-based therapeutic strategies show great potential for MS therapy, Jeffrey Cohen, MD, Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, told MD Magazine.
“However, there still are numerous methodological challenges,” Cohen said.
Although I/AHSCT has been more thoroughly investigated than other approaches, the report notes that most studies were small or single center case series with differing populations, protocols and outcome measures. That is about to change, Cohen said, with a multi-center clinical trial in the UK and another in the US now underway.
"The UK trial is the STAR-MS multi-center trial with the lead site at Sheffield Teaching Hospital, and the US Trial is an NIH-funded multi-center trial, BEAT-MS,” Cohen said. “Both are randomized studies comparing I/AHSCT versus best available disease modifying therapy.”
Enhanced endogenous cell therapy including mesenchymal stem cells (MSCs) also considered at the conference potentially offer a greater therapeutic role than conventional cell replacement.
The report describes the possible mechanisms of action as "offering the prospect of ameliorating a number of the differing pathological processes contributing to tissue damage in multiple sclerosis."
Some of the studies have used mixed/unseparated cells, while others, including Cohen's group, have administered purified and culture-expanded MSCs. The report points out, however, that a lack of comparative studies of different cell products and of in vitro markers that relate to therapeutic efficacy “preclude recommendations on the optimal cell production protocol."
The consensus report indicated that if enhanced endogenous cell therapy evidences benefits in future trials, it could lead to molecular treatments using the principle effectors elaborated by the introduced cells.
That future prospect is complicated by numerous factors including the inconsistent activation of MSC therapeutic capacities in different populations, according to the report.
"This process is likely dynamic, with the profile of administered cells and of those infiltrating tissues evolving with the progress of each individual disease or injury,” the report read. “It may be challenging to reproduce this by administering molecules rather than cells.”
An additional cell-based strategy is the use of oligodendrocyte progenitor cells and induced pluripotent cells with the potential to repair and remyelinate, not only damaged neurons in MS, but in conditions such as traumatic brain and spinal cord injury.
The conference pointed to research which has detected genetic modifications in the cells, however, raising the possibility of aberrant tissue formation or malignant transformation after cell transplantation. The consensus report called for additional research to design cell lines that are safe for human use.
The consensus report also included a strong warning that these cell-based strategies are experimental, and should be administered within research settings and in clinical trials, despite some availability outside these environments.
"Often such clinics are — for obvious reasons — based in jurisdictions with less stringent medical regulatory structures, and so there can often be little if any assurance of the expertise, quality of care (or even hygiene), or ethical standards of the provider center, which is often unwilling or unable to seek more traditional financial support for their 'research',” the report read.
The study, "Cell-based therapeutic strategies for multiple sclerosis," was published online in the November issue of Brain.