New Directions in MS Research: New Therapeutic Approaches
Based on encouraging results from a variety of studies, clinical trials are now starting to enroll patients using three different broad classes of stem-cell-based approaches.
The first stem-cell approach is hematopoietic stem-cell transplantation (HSCT). This form of stem-cell therapy first requires a wiping out or “ablation” of the immune system, typically with high-dose chemotherapy. This intensive course of chemotherapy destroys most blood cells as well as the bone marrow, where blood cells are formed. Then a patient’s own hematopoietic stem cells can be transplanted, in an effort to completely reset the immune system in the hopes of abolishing the autoimmunity responsible for MS.
One trial of this technique is the High-Dose Immunosuppression and Autologous (stem-cell) Transplantation for Multiple Sclerosis (HALT MS) Study, for poor prognosis multiple sclerosis. The HALT Phase II study was conducted in 25 patients with highly active RRMS who had failed conventional therapy. The two-year follow-up results of the HALT study were reported in 2013.95 The treatment induced profound immune suppression and a high rate of sustained remissions at two years.
Further interim results covering three years of the study were reported in 2014.96 A total of 78 percent of subjects had no new disease activity. Treatment failed in five subjects, and two deaths occurred. There have been 130 adverse events that were severe or life-threatening, most relating to low blood counts induced by the treatment approach. Study participants will be followed for five years in total to see how long the benefits of this treatment may continue, and if the safety profile proves to be manageable.
A study in Sweden97 found a high pro-portion of patients with aggressive, relapsing forms of MS, were free from disease activity following hematopoietic stem-cell trans-plantation (HSCT). A group of 41 patients participated, with a mean annualized relapse rate of 4.1 in the year preceding treatment, which means that on average, each was experiencing four relapses in one year.
With a mean average follow-up time of nearly four years (47 months) after receiving the HSCT procedure, 89 percent of the participants were relapse-free and 77 percent of the participants had no disability progression, as measured by EDSS. In addition to the serious though expected side effects, including sepsis and fever, a small number of patients experienced other adverse events. These included a reactivation of herpes zoster in seven patients and thyroid disease in four patients; no deaths occurred in this trial.
A second type of stem-cell therapy utilizes mesenchymal stem cells, which can be derived from tissues other than bone marrow and do not require a “wiping out” of the immune system for their use. In a phase IIa study,98 10 patients with SPMS with involvement of the visual system were infused with self-derived (autologous) mesenchymal stem cells.
The researchers found an improvement in visual function, as well as an improvement in other laboratory and imaging measures of optic nerve function. There were no serious adverse events or deaths. Although the mechanism by which mesenchymal stem cells exert their beneficial effects has not been fully worked out, these cells do not need to penetrate into the nervous system and grow at the site of lesions, such as the optic nerve. The results of this study were suggestive of a more generalized neuroprotective effect; this effect is discussed in the next section.
A third approach to investigating stem-cell therapy, and perhaps the one most in-line with the commonsense notions about the potential uses of stem cells, is to utilize them for the purpose of directly regenerating myelin that has been damaged by MS. This approach requires multiple complex steps in order to be successful. Techniques must be employed to: harvest a patient’s stem cells; grow and multiply them; administer them to the patient; ensure that they get into the central nervous system; ensure that they are not destroyed by the body’s own immune system; ensure that they grow to become the correct type of cell (for instance, to restore myelin); and to ensure that they do not overgrow or cause damage to the nervous system.
This approach to stem-cell therapy is being investigated in an open-label Phase I clinical trial99 announced in fall 2013. This single-center trial plans to enroll 20 patients with progressive MS, and will infuse doses of stem cells harvested from the patients’ own bone marrow directly into the cerebral spinal fluid (CSF), typically done via lumbar puncture, repeatedly over six months.
As an open-label study, the primary endpoint will be to determine the safety of this approach. Potential subsequent investigations may pursue efficacy, ascertain the optimal dose and route of administration, and identify patients most likely to benefit from this therapeutic approach. It is important to recognize that, as an open-label, uncontrolled, unblinded Phase I study, this project is at the earliest stages of experimental human research. It cannot, by its very design, provide meaningful information about efficacy, despite what has been reported by the media.