Stem Cell Therapies
New Directions in MS Research
Researchers around the world continue to explore the role of stem cells in treating multiple sclerosis (MS).
Most stem cell research in MS focuses on autologous hematopoietic stem cell transplantation, or aHSCT. The term “autologous” means that the cells are taken from the patient’s own body. Hematopoietic stem cells have the ability to generate new immune cells and blood cells.
The goal of stem cell transplantation in MS is to “re-boot” the immune system so that it stops the mounting inflammatory responses harmful to the brain and spinal cord. Physicians pursue this goal through a sophisticated process that typically begins with giving a patient several days of chemotherapy. This treatment prompts the bone marrow to produce stem cells and release them into the blood. Blood containing these stem cells is then drawn from a vein and stored.
Next, the patient is given another set of chemotherapy drugs to suppress or even entirely wipe out his or her immune system. The patient is carefully monitored during and after this phase of treatment to guard against infection and other risks associated with reduced immunity. The stem cells taken from the patient’s blood earlier are then transplanted back into the patient by intravenous infusion.
These stem cells begin to re-build the body’s immune function over the course of a few months, with the hope being that the newly constituted immune system will “tolerate” the brain and spinal cord rather than generate an inflammatory response, which leads to the myelin sheath damage and outward symptoms that are the hallmark of MS. The transplantation process typically involves a prolonged hospital stay.
Just a few weeks before the COVID-19 pandemic came to dominate his every waking moment, Anthony S. Fauci, MD, announced that the government’s National Institutes of Health (NIH) had launched a clinical trial to test aHSCT against the best available biologic therapies for severe forms of relapsing MS.74 In announcing the trial in early January, Dr. Fauci said, “aHSCT has the potential to halt the progress of relapsing MS, eliminate the need for a person to take life-long medication, and allow the body to partially regain function. However, we need to be certain that the benefits of this form of treatment outweigh its serious risks.”
The NIH noted that prior studies have suggested that aHSCT may be an effective and durable treatment for people with MS, but the therapy has never been formally compared head-to-head with relatively newer, so-called “third-line” MS medications, which the government agency noted are highly effective but can have harsh side effects. Treatment with aHSCT also carries the risks of serious side effects, and even death.
Given these risks and benefits, the NIH continued, investigators will seek to determine whether aHSCT is an appropriate treatment option for people with severe forms of relapsing MS who would otherwise receive one of the best available third-line biologic drugs. The trial is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the division of the NIH that Dr. Fauci leads.
The trial is called BEAT-MS (BEst Available Therapy versus autologous hematopoietic stem cell transplant for Multiple Sclerosis). It is being conducted by the NIAID-funded Immune Tolerance Network (ITN) in collaboration with the Blood and Marrow Transplant Clinical Trials network (BMT CTN). The BMT CTN is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute, both components of NIH. The trial is being led by Jeffrey A. Cohen, MD, a professor of neurology at the Cleveland Clinic Lerner College of Medicine and the director of the Experimental Therapeutics Program in the Mellen Center for Multiple Sclerosis Treatment and Research at the Cleveland Clinic.
BEAT-MS will enroll 156 adults ages 18 to 55 years at 19 sites in the United States and the United Kingdom. Participants will be randomly assigned to receive either aHSCT or one of the best available high-efficacy biologic drugs, and will be followed for six years. The neurologists who periodically examine the participants and assess their level of disability will not know which type of treatment they were assigned.
The main outcome investigators will measure is how much time elapses between a participant’s assignment to a treatment strategy and MS relapse or death from any cause, if either of these occur, during the first three years of the follow-up period. The researchers will also examine the mechanisms of action of the two treatment strategies and will compare the newly developing immune systems of participants who receive aHSCT with the immunologic features of study participants who receive the best available biologic drugs. In addition, investigators will compare the effects of the two treatment strategies on other measures of disease activity and severity, cost-effectiveness in terms of health care costs and individual productivity, and participants’ quality of life.74
At the September 2019 annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Stockholm, Sweden, several other teams of researchers reported on their experience with stem cell transplantation. One of the largest stem cell transplantation studies reported at ECTRIMS yielded disappointing results in terms of its primary endpoint, but offered some potentially encouraging news nonetheless.
The Phase II MESEMS trial was a multi-center, international study that included 144 people with MS. The trial was double-blinded, meaning that neither the physician nor patient knew whether or when the patient was receiving transplanted stem cells or placebo. The study also had a “cross-over” design, meaning that one group of participants received transplanted stem cells at the start of the trial, was observed for 24 weeks, and then received placebo for 24 weeks.
Participants in the other group received placebo for 24 weeks and then underwent transplantation, after which they were observed for 24 weeks. The purpose of this “cross-over” approach is to see how all patients do on six months of placebo and during the six months after transplantation. The patients were treated with their own mesenchymal stem cells. Mesenchymal stem cells are adult cells derived from bone marrow that have the ability to develop into many kinds, but not every kind, of human cell.
The primary endpoint of the MESEMS trial was reduction in the number of gadolinium-enhancing lesions on imaging compared to placebo. On this foremost measure, there was not a statistically significant difference between stem cell transplantation and placebo. However, the results of a secondary endpoint, annualized relapse rate (ARR), were more promising. Although the study did not show statistical significance based on the criteria specified at the outset of the trial, stem cell transplantation showed a 36% reduction in the ARR relative to placebo. While the results have to be interpreted with caution because they did not achieve statistical significance, one of the study’s investigators termed them a “strong signal.”75
The results of the MESEMS trial reinforce the fact that while medical research inexorably moves forward, it rarely does so in a perfectly straight line, or at the pace and with the near-term results that clinicians and patients would wish.
Investigators from Uppsala University Hospital in Sweden reported that 93% of people with MS who underwent aHSCT at their institution, between 2004 and early 2019, had no disease progression over an average 3.9 years of follow-up. Further, 87% of the 81 people studied had no relapses during that follow-up period, and 74% had no new lesions appear on MRI.76 The study included 56 women and 25 men, and 95% of the participants had relapsing forms of MS. Their median age at transplantation was 29 years, and the average disease duration prior to the procedure was six years. Study participants had received a median of two MS therapies prior to aHSCT. Roughly three-quarters of these individuals received a low-intensity chemotherapy regimen prior to transplantation, while the remainder received an intermediate intensity-conditioning regimen.
The group’s annualized relapse rate (ARR) declined from 2.2 in the year preceding transplant to 0.0022 afterwards. Further, 63% of participants saw an improvement in their Expanded Disability Status Scale (EDSS) scores. Another 35% of those taking part in the study had an unchanged EDSS score, while 2% worsened. No patients died during the follow-up period.76
A study examining outcomes in 30 people with relapsing forms of MS who underwent stem cell transplantation in Norway, between 2015 and early 2018, reported similarly favorable results. The study’s primary outcome measure was the percentage of people who achieved “No Evidence of Disease Activity-3” (NEDA-3), which was defined as no clinical relapse, no MRI activity, and no Expanded Disability Status Scale (EDSS) progression post-transplant.77
Eighty-three percent of the participants achieved this NEDA-3 status. Additionally, 43% had a sustained improvement in their EDSS score, 33% were working full-time after transplantation as compared to only 3% beforehand, and no patients received disease-modifying treatment after stem cell transplant.
While no individuals in the study died, and no serious treatment-related complications were reported, 17% of those treated were diagnosed with autoimmune thyroid disease following transplantation, and 43% of the women in the study reported not having a menstrual period for more than 12 months after transplant.77
Meanwhile, investigators in Hamburg, Germany used a prospective case-control approach to compare outcomes between aHSCT and the disease-modifying therapy (DMT) Lemtrada® (alemtuzumab) in 40 people with highly inflammatory MS. Nineteen of the patients received aHSCT. Of the people in that group, 12 had relapsing forms of MS, while seven had progressive MS. Five of the 21 individuals receiving Lemtrada had an underlying chronic disease.
The two groups were similar in terms of gender, age, EDSS score, number of prior therapies, and other factors. Disease duration, however, was longer in the Lemtrada group, while relapse activity in the two years prior to treatment initiation was lower.
The study’s primary outcome measure was no evidence of disease activity (NEDA), meaning no clinical relapse, no MRI activity, and no Expanded Disability Status Scale (EDSS) progression. Average follow-up time was just under five years for the stem cell transplant group and just over two years for the individuals receiving Lemtrada. The researchers reported that significantly more patients receiving stem cell transplants achieved the goal of NEDA compared to people treated with Lemtrada, although no difference was seen in confirmed disease progression, as measured by EDSS scores, between the two groups.78