New Directions in MS Research: New Therapeutic Approaches
Based on encouraging results from a variety of studies, clinical trials are now starting to enroll people using three different broad classes of stem-cell-based approaches.
The first stem cell approach is hematopoietic stem cell transplantation (HSCT). Hematopoietic stem cells from the bone marrow are the common precursor cells from which both red and white blood cells originate. The HSCT requires multiple steps. First, stem cells, which circulate throughout the bloodstream, are collected by taking blood from the patient. The stem cells are obtained by filtering the blood, while the other cells – especially the white blood cells that are responsible for MS attacks – are removed. These stem cells are then set aside and preserved while a wiping out or “ablation” of the immune system, typically with high-dose chemotherapy, occurs.
This immunosuppressive chemotherapy regimen is, in essence, the “MS treatment” phase of the HSCT procedure. This intensive course of chemotherapy destroys most blood cells as well as the bone marrow, where the blood cells are formed. Then, the patient’s own hematopoietic stem cells can be transplanted back into the blood to rebuild the immune system. HSCT is often thought to bring about a “reset” of the immune system, back to its original purpose of guarding against infection and away from inappropriately attacking itself.
One trial of this technique is the High-Dose Immunosuppression and Autologous (stem cell) Transplantation for Multiple Sclerosis (HALT MS) Study, for poor-prognosis MS. The HALT Phase II study was originally conducted in 25 individuals with highly active RRMS who have failed conventional therapy. The two-year follow-up results of the HALT study were reported in 2013.59 The treatment induced profound immune suppression and a high rate of sustained remissions at two years.
Further results covering five years of the study were published in 201760; 69 percent of the participants had no new disease activity (compared to 78 percent stability at three years). At three years, treatment had failed in five subjects, and two deaths occurred; one attributed to MS progression and one secondary to asthma. In the five-year follow-up, one additional death was reported in an individual who had disease progression and it was reported that seven participants had developed either MS progression (n=2), new relapse (n=3), or new MRI activity (n=2). A total of 130 adverse events that were severe or life-threatening were previously reported, most relating to low blood counts induced by the treatment approach. Two suicide attempts, neither completed, occurred in participants who reported to have an unremarkable history before the HSCT, meaning that neither had a history of psychological problems that might lead to suicide attempts. A total of 15 additional adverse events were reported in the most recent study, though none were of the most severe type. The results of the HALT MS study are certainly intriguing, yet they are tempered by the fact that three of 24 participants had died at five years, with multiple other significant adverse events reported.
Another study conducted by researchers in Canada was published in 2016. This study used HSCT in 24 individuals with aggressive MS and followed patients for three to 13 years. One early participant in this study died of transplant-related complications. This death and another life-threatening infection in a second individual prompted the study authors to change the protocol by decreasing the dose of one of the chemotherapy drugs that was given in order to decrease the risk for toxicity and infection. The authors reported that participants did not have any new relapses or MRI activity after transplantation. Overall, 70 percent of patients remained stable, with the other 30 percent showing evidence of disease progression.61 Interestingly, researchers found a delayed effect of HSCT on the rate of brain atrophy; at three years participants had rates of brain atrophy similar to untreated MS patients, but later on decreases in brain volume were more similar to that of aging persons without MS.
A study in Sweden published previously62 found a high proportion of people with aggressive, relapsing forms of MS, were free from disease activity following HSCT. A group of 41 individuals participated in this study. They had a mean annualized relapse rate of 4.1 in the year preceding treatment, which means that on average, these individuals with very active disease were each 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 participants were relapse-free and 77 percent of 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 people 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.
In 2015, Burt and colleagues published the results of a larger study, giving data on 123 individuals with RRMS and 28 people with SPMS who underwent HSCT over a 10-year period.63 The study was open-label, meaning that everyone in the study received the treatment and thus did not have a comparison group. The findings included a significant decrease in relapse rates and new MRI lesions. Four-year data showed that 80 percent were relapse-free and 87 percent were free of progression. Importantly, a significant improvement in disability scores was also seen for those individuals in which long-term data were available.
While the data from this study are encouraging, it is important to point out the open-label nature of this study that may have led to biased results. Also, this method of treatment is not without risks. The administration of potent chemotherapy and the ablation of the bone marrow put patients at risk for infections and other complications. In this trial, the main adverse events were related to the development of thyroid disease and other autoimmune conditions. Infections were not common, and those that did occur were not severe. Two cases of cancer occurred post-transplant, but it is unknown if there was any causal relationship with the HSCT. The group that carried out this study is currently conducting a randomized trial of HSCT versus standard MS therapies.
A second type of stem cell therapy utilizes mesenchymal stem cells (MSC). Unlike HSCT, MSCs are not used to “reset” the immune system. Instead, the aim of MSC therapy is to provide stem cells that have the potential to develop into cells that may promote the repair or regeneration of the nervous system. Importantly, MSC therapy does not require high doses of chemotherapy to “wipe out” the immune system, thus it may be a safer option.
In a Phase IIa study64 published in 2012, 10 people with SPMS with involvement of the visual system were infused with self-derived (autologous) mesenchymal stem cells (MSCs). In order to obtain the MSCs, investigators removed bone marrow from the patient. Then, they filtered out any cells that promote inflammation, and the remaining stem cells were grown in larger numbers and then given back to the patients through an infusion.
The researchers found an improvement in visual function, as well as an improvement in other laboratory and imaging measures of optic-nerve function. No serious adverse events or deaths occurred. Although the mechanism by which mesenchymal stem cells exert their beneficial effects has not been fully understood, 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.
Multiple other Phase I or Phase II trials of mesenchymal stem cell therapies are currently either in the planning stages or recruiting, including a collaborative effort named MESEMS.65 MESEMS is an international group of eight independent study centers that have created a shared study design in order to be able to increase the power and significance of their results. The group plans to enroll 160 patients in total, with the goal of obtaining the data necessary to plan a more definitive Phase III trial.
A third approach to investigating stem-cell therapy, and perhaps the one most in-line with the common-sense 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 an individual’s stem cells, grow and multiply them, administer them to the individual, 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 was investigated in an open-label Phase I clinical trial,66 which has been completed, but the full results have not been published. This small, single-center trial of 20 individuals with progressive MS involved infusing 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, determine optimal dose and route of administration, and identify people 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.