Clinical trials examine stem cell transplants in relapsing-remitting MS


Stem cell therapy is a broad and multifarious field that, for multiple sclerosis (MS), is still experimental. But in the landscape of new and upcoming clinical trials, there are notable shifts underway in the stages and goals of research–possible pivot points, some experts say–that may ultimately help fill therapeutic gaps.

Immunoablation followed by autologous hematopoietic stem cell transplantation (I/AHSCT) is moving on to Phase 3 randomized controlled trials for relapsing-remitting (RR) MS, having demonstrated what investigators say is substantial and sustained efficacy in mostly small, single-center uncontrolled trials. Here, the stem cells assume roles in an anti-inflammatory approach that’s similar to that of the currently available disease-modifying medications (DMTs). Researchers hope that the new trials will help define where the aggressive, experimental therapy sits relative to DMTs, which have made great strides but still are only partially effective in preventing inflammatory damage to the central nervous system.

Credit: MS Research Australia

Research on mesenchymal stem cells (MSCs), in the meantime, is moving past the realm of small phase 1 and proof-of-concept studies into trials that will look more directly for benefit in progressive MS—mostly significantly, at their ability to help repair damage to the nervous system in patients with primary or secondary progressive forms of the disease. None of the available DMTs directly promote repair.

“The biggest question about hematopoietic stem cell transplant, besides fine-tuning specifics of the technique, is whether it should be considered not only as a last resort but perhaps as an alternative to some of our other proven potent therapies [for relapsing-remitting MS],” said Jeffrey A. Cohen, director of experimental therapeutics at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research.

Jeffrey A. Cohen

With respect to MSCs, “the important thing we’ve learned from all the studies thus far is how many more unanswered questions there are than answers,” he said. “We still have very fundamental technical questions, like how many stem cells should you inject? Where should you inject them? Where should they be isolated from? And how should they be prepared? Even so, we’re at a sort of pivot point, where we’ve worked out at least some of the technical issues, and now work is going to accelerate.”

At the most basic level, in the meantime, investigators are working on generating oligodendrocyte precursor cells (OPCs) from human skin cells—or, in two steps, creating induced pluripotent stem cells from skin cells and then converting them to OPCs. In either case, the idea is to create an autologous source of myelin-forming oligodendrocytes that, once injected into the central nervous system, could augment remyelination in MS.


Hematopoietic stem cell transplantation after immunoablation

It is clear at this point that the patients who are most likely to benefit from I/AHSCT have RRMS, which is highly inflammatory, rather than long-standing progressive disease, in which neurodegeneration features much more prominently. The treatment essentially “reboots” the immune system by ablating it with chemotherapy and then replacing it with a new immune system that’s expected to behave normally, with tolerance for the central nervous system. Hematopoietic stem cells are harvested and frozen prior to immunoablation and then reinfused to shorten the so-called aplastic phase and promote hematopoietic reconstitution. Whether the cells play any other role—in addition to this “rescue” work—is uncertain, sources say.

Participants of a 2015 consensus workshop, the International Conference on Cell-Based Therapies for Multiple Sclerosis, generally agreed that future trials on I/AHSCT should enroll patients who are relatively young (e.g. 50 years or less), whose time from diagnosis is relatively short (e.g. within about 5 years), and whose RRMS is active, as reflected by clinical relapses and MRI lesion activity, despite treatment with DMT. Somewhat controversial, given the aggressive nature of the approach, is the recommendation that patients be ambulatory despite accumulating disability (Brain 2017:140:2776-2796). The consensus workshop was held under the auspices of the International Advisory Committee for Clinical Trials in Multiple Sclerosis.

“These are patients who are getting worse despite the approved therapies, but who are not so severe that it is too late [for impact from the treatment],” said Dr. Cohen, co-chairman of the international committee.

There was a lot of debate about whether to focus on highly sensitive measures of inflammation, for instance, MRI lesion activity…or to look at disability, which is highly meaningful but takes a large number of people followed for a long time to notice differences.

Dr. Cohen will lead one of at least two randomized, controlled, multi-center trials that are being planned for launch sometime in 2019. His trial is funded by the National Institutes of Health and is being designed to compare I/AHSCT with approved monoclonal antibody therapies (“best available therapy”) in approximately 150 patients. Another RCT being planned in the United Kingdom will pit I/AHSCT against alemtuzumab (Lemtrada), Dr. Cohen said. “Hopefully,” he said, “we’ll get definitive information about how transplant stacks up against what currently are our best available therapies.”

Study design has been challenging, Dr. Cohen said. For one, there are questions about the extent to which early inhibition of inflammatory activity correlates with long-term disease outcome. “There was a lot of debate about whether to focus on highly sensitive measures of inflammation, for instance, MRI lesion activity…or to look at disability, which is highly meaningful but takes a large number of people followed for a long time to notice differences,” Dr. Cohen said. “The approach we decided to take, at least in terms of primary outcome, was a compromise.”

The study will look primarily at time to first MS relapse and the proportion of patients who are free of relapse, but it will also include a wide range of secondary outcomes, including various measures of disease activity and disability, various MRI measures including brain atrophy, and patient-reported quality of life. A comprehensive health economic analysis will be conducted as well, Dr. Cohen said, and researchers will look for possible effects of prior DMTs and various co-morbidities on outcomes.

Also challenging for study design has been lingering debate over intensity of the “conditioning” regimen used to knock out the faulty immune system. A multi-center phase 2 Canadian trial that employed a high-intensity regimen (busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin, or rATG) showed potent and durable outcomes but also saw 1 of the 24 patients die of transplant-related complications (Lancet 2016; 388:576-85). On the other hand, in a closely-watched international study employing a low-intensity regimen (cyclophosphamide and rATG), the treatment appears to have been better tolerated, with no severe toxicities or deaths, but outcomes may be less efficacious and durable, sources said. Final results from this trial, led by Richard Burt, MD, of Northwestern University, are expected soon.

The new NIH study will employ an intermediate-intensity chemotherapy regimen known as BEAM (carmustine, etoposide, cytarabine, and melphalan)—a choice that takes into account the experiences in these two key trials as well as an earlier NIH-sponsored phase 2 trial, called the HALT-MS study, which similarly employed BEAM, Dr. Cohen said. Among the 21 participants who completed the HALT-MS study, approximately 91% were free of disability progression during a median follow-up of 62 months, and approximately 87% and 86% were free of clinical relapse and new MRI activity, respectively. Three patients (of the 24 total participants) died at least a couple years post-transplant, but each had experienced worsening of MS, and no death was treatment-related, the study investigators reported (Neurology 2017; 88:1-11).

Mark S. Freedman, MD, who co-led the Canadian trial of I-AHSCT involving high-intensity immunosuppression, cautions that stem-cell transplant surgeons who operate in the field of oncology have been “softening” the conditioning regimens for a variety of clinical reasons that are not applicable to neurological disease and patients with RRMS. He credits the finding of no relapses and no new MRI activity during a median follow-up of 6.7 years (and up to 13 years) in his trial to the high-intensity conditioning regimen, and said follow-up of patients who received I-AHSCT outside of the trial has shown “no renewed disease activity” for up to 20 years now.

Moreover, some patients are achieving substantial recovery of neurologic function post-transplant, said Dr. Freedman, director of the multiple sclerosis research unit at the Ottawa Hospital-General Campus and professor of medicine-neurology at the University of Ottawa. In the trial, 35% had sustained improvement in the Expanded Disability Status Scale (EDSS) score.

Dr. Mark S. Freedman

Credit: MS Society of Canada
MEsenchymal Stem cell therapy for CAnadian MS patients (MESCAMS)

“Many patients had deficits I thought they’d never recover, like really bad ataxia or uncoordinated gaits,” he said. “In the early phases of MS, there’s always an attempt at repair. But it gets very hard to repair over time as inflammation keeps hitting the nervous system…As soon as you eliminate the inflammation, the repair crews can go in and fix this. I think that’s what we’re seeing.”

[Interestingly, any progression of disability that occurred among the trial participants happened within the first two years after transplantation. “Then, after two years, there was nothing,” Dr. Freedman said, “which tells us that the inflammation of today doesn’t necessarily translate into disability of today.”]

Dr. Freedman’s study and some other trials have also involved graft processing—a selection and/or removal of cells from the hematopoietic stem cell harvest. In the Canadian trial, CD34-expressing stem cells were immunomagnetically selected and then purified, with other mature, possibly autoreactive immune cells eliminated in hopes of preventing any transfer of autoimmunity. The current international consensus is that graft processing is probably unnecessary, Dr. Cohen said. But in Ottawa, Dr. Freedman and his colleagues are maintaining this part of the regimen just in case it’s helpful; the process is relatively inexpensive and convenient there, he noted.

In the meantime they are working on securing funding for a new study that compares I/AHSCT to some of the newer DMTs, and in clinical practice they are offering I/AHSCT to patients who have disease that is aggressive but less active than it was in trial participants. “We’ve opened our criteria a bit for the last 40 or so patients [who’ve received I-AHSCT],” Dr. Freedman said. “These are patients who…even when we pull out some of the stronger agents to begin with, they’re quickly showing us that [DMT] doesn’t [control] the disease.”

I/AHSCT is the one stem cell-based therapy for MS that, despite an experimental status, is sometimes used outside of clinical trials without rankling too many feathers in the research community. According to the 2017 review article in Brain, participants of the International Conference on Cell-Based Therapies for MS “acknowledged that there are rare patients with highly aggressive MS not adequately controlled by available DMTs for whom this approach can be appropriately considered as part of clinical practice.”

Outcomes should be submitted to existing registries and ultimately published, the review authors emphasize. Indeed, registries and the networks that establish them can sometimes offer a more efficient approach than clinical trials—even the large multi-center ones.

The Autoimmune Disease Working Party of the European Society for Blood and Marrow Transplantation maintains a registry of patients with MS and other autoimmune disorders undergoing I/AHSCT, for instance. So does the Autoimmune Diseases and Cellular Therapies Working Committee of the Center for International Blood and Marrow Research.

Credit: Rose Spear/flickr/CC BY 2.0
Human mesenchymal stem cells attached to fibrin (5 mg/mL) within a porous network of ferritic stainless steel intended for implant coatings. 

Mesenchymal stem cells

Researchers have had the most experience with I-AHSCT in MS than any other stem-cell approach–more than 20 years of research–but it’s the utilization of adult mesenchymal stem cells (MSCs) that garners more attention. The cells are easily accessible, and their main application–in addition to modulating pathogenic and inflammatory immune responses–is to promote repair of a damaged nervous system. Most of the commercial stem cell clinics are offering or claiming to offer some version of MSC transplantation—a practice that many reseachers and the Food and Drug Administration say is premature and potentially dangerous (see sidebar).

Credit: Libertas Academica

MSCs can be isolated from the bone marrow, adipose tissue, cord blood, and most if not all other tissues. So many different cell products have been studied and different cell production protocols utilized for in-vitro, animal and early clinical studies that the International Conference on Cell-Based Therapies for MS found it difficult to make any specific recommendations for future research. The phase 2 studies that are currently underway, the workshop’s review paper says, “should clarify whether this approach is efficacious for MS and in what phase.”

Credit: The Ottawa Hospital
Can a new immune system halt MS and allow repair?

At this point, eyes are partly on a nine-country phase 2 study that is scheduled to release pooled data in the spring of 2019. Patients in the international crossover study have been randomized to receive a single intravenous infusion of autologous, bone-marrow-derived, expanded MSC at the start of the study or at 24 weeks. Those not receiving MSC at the time have received an equivalent volume of suspension media (placebo). In addition to reaffirming safety, the primary outcome is reduction in the total number of gadolinium-enhancing lesions by MRI. But a number of other measures are looking at clinical efficacy (incidence of relapses and disability progression) and also at the potential of MSC to stimulate neuroprotection or myelin repair.

Dr. Freedman is the principal investigator of the 40-patient Canadian arm of the study, coined MESCAMS for Mesenchymal Stem Cells for Canadian MS Patients, which has included patients with RRMS as well as those with progressive disease. “We want to know, is tissue that isn’t completely scarred…better repaired in the presence of these cells than [when the cells are not present]? These are hard questions to answer, since no one has really shown how to measure repair,” he explained.

“We’ve thrown everything at our patients in terms of trying to measure repair–sophisticated MRI imaging on subgroups, lots of immunology, neurophysiology, and neurocognitive studies…in hopes of getting some signal [of possible repair] that can help us to move forward” in further studies if results are positive, Dr. Freedman said. “We want to know, is there a repair signal? When does it occur, and does it fade?”

MSCs have been shown in in-vitro and in-vivo preclinical studies to release anti-apoptotic, anti-oxidant, and trophic factors, all of which can provide neuroprotection. But there’s much more to learn about their potential mechanisms of action. Bruce F. Bebo, Jr., PhD, executive vice president for research at the National Multiple Sclerosis Society, said it is unlikely that MSCs travel to axons and directly repair myelin, and quite likely that the MSCs secrete factors that not only inhibit the immune response but that prompt or support the nervous system to repair itself. That, he said, is the “leading hypothesis” regarding how MSCs can be beneficial for MS. “They could prove to be a good one-punch to inhibit inflammation and at the same time promote repair,” he said.

In another closely watched phase 2 study, investigators at the Tisch Multiple Sclerosis Research Center of New York are taking a different approach to MSC therapy, creating specialized MSC-neural progenitor cells and injecting them intrathecally in an attempt to promote repair and regeneration in patients with progressive MS.

Investigators at the Center have long worked with MSC-NP cells–isolating MSCs from the bone marrow, expanding them ex-vivo in MSC growth medium, and then culturing them in neural progenitor maintenance medium—and have shown that the cells express and secrete trophic factors that mediate various aspects of neural repair. Saud A. Sadiq, MD, director and chief research scientist at the Center, has also long focused his research on MS on the cerebral spinal fluid and the intrathecal space.

“Over time we could move to a more convenient route, but for now, the intrathecal route was chosen because that’s the site of the pathology. And the central nervous system is such a protected environment, it takes away the burden of somehow having to get the cells through the blood-brain barrier,” said James A. Stark, MD, a neurologist and director of clinical trials at the International Multiple Sclerosis Management Practice, which operates alongside the Tisch MS Research Center.

Credit: Tisch Multiple Sclerosis Research Center

Dr. James A. Stark

A phase 1 clinical trial, the findings of which were just recently published, involved 3 separate doses of autologous MSC-derived neural progenitor cells (MSC-NP) spaced 3 months apart in 20 patients. It found not only that the treatment was safe and well tolerated, but that there was some improvement in EDSS scores. In addition, 70% and 50% of the study participants demonstrated improvement in lower extremity muscle strength and bladder function, respectively. 

“While studies in mice had shown that cells injected into the lower back actually migrated into the brain, only one of the patients [with improved muscle strength] had improvement with arm function,” said Dr. Stark. “It could be that the cells aren’t traveling enough, or that whatever effect they’re exerting is local, close to where we’re doing the spinal tap.”

The new phase 2 study is a randomized double-blind, placebo-controlled crossover study in which 50 patients will receive 6 intrathecal injections of autologous MSC-NPs at 2-month intervals in one year, and 6 lumbar punctures as placebo treatment in the second year. The study will focus on patients with slightly less disability than in the phase 1 study, Dr. Stark said. And while the dosing will be the same —up to 1 x 107 cells per dose—participants will receive the stem-cell injections more frequently and over a longer period of time.

The EDSS will serve as the primary outcome measure, and a variety of secondary endpoints—including cognitive and quality-of-life measures—will also measure efficacy.

Like MSCs, myelin-making oligodendrocytes are a much-talked-about cell in the MS research community. Here, however, the focus is on direct cell-remyelinating strategies rather than on support of repair. “They’re the most abundant dividing cell in the nervous system, and they have a tremendous ability to repair in the early stages of MS,” Dr. Bebo said. “They’re able to migrate to the areas of damage and able to repair myelin…But as the disease progresses, these cells seem to slow down and become unable to repair.”

Oligodendrocyte progenitor cells (OPCs) can be isolated from the fetal brain–an approach that shows promise but is problematic for a host of practical and ethical reasons. There’s growing interest, therefore, in generating them from skin cells or, alternatively, in generating them from induced pluripotent stem cells (iPSCs) that are derived from the recipient. Researchers believe at this point that direct injection into the central nervous system will be necessary for the cells to access demyelinated lesions, and a phase 1 trial is being designed to test the feasibility and safety of doing just this, Dr. Bebo said.

Some studies of human iPSCs have detected frequent genetic modifications, raising concerns about possible post-transplantation malignancy or formation of aberrant tissue. The concept—the utility of exogenous OPSs—also needs to be proved. The problem, said Dr. Bebo, may not be the lack of OPCs near demyelinated areas but “factors in the environment that don’t allow the OPCs that live there to promote repair.” Finding ways to pharmacologically manipulate the environment in ways that promote remyelination may hold more promise, he said. But in the meantime, “we’re going to pursue every promising possible [stem cell] approach.”

Credit: Jurjen Broeke/Wikimedia Commons/Public Domain

Dr. Cohen reported personal compensation for consulting for Alkermes, Biogen, Convelo, EMD Serono, ERT, Gossamer Bio, Mapi, Novartis, Pendopharm, and ProValuate; speaking for Mylan and Synthon; and serving as a Co-Editor of Multiple Sclerosis Journal – Experimental, Translational and Clinical.

Dr. Freedman reported receiving personal fees from Genzyme, Merck Serono, Bayer, Biogen Idec, Teva Canada Innovation, Opexa, Novartis, and Chugai.

Dr. Bebo reported no conflicts of interest.

Dr. Stark reported no financial disclosures other than his employment with the IMSMP, which is the clinical practice associated with the Tisch MS Research Center.

The perils of commercial stem cell clinics

Outside of the world of clinical trials, there is a growing U.S. industry of stem cell clinics engaged in direct-to-consumer marketing of untested stem cell interventions–many of which, researchers say, do not appear to have met the criteria for exemption from the Food and Drug Administration’s premarket approval requirements.

In 2017, the FDA finalized guidance documents relating to stem cells, one of which clarifies the FDA’s interpretation of two concepts–“minimal manipulation” and “homologous use”—that are used to establish when a product is or is not subject to the Agency’s premarket approval requirements (). The FDA also announced that year that it was increasing enforcement of regulations and oversight of stem cell therapies and regenerative medicine.

“The regulations are now pretty clear on what you can do without an [Investigational New Drug Application],” said Jeffrey A. Cohen, director of experimental therapeutics at Cleveland Clinic’s Mellen Center for Multiple Sclerosis Treatment and Research. The question, according to Dr. Cohen and other researchers and ethicists who have written about the stem cell clinic industry, is whether the FDA will act strongly and consistently enough to enforce what FDA Commissioner Scott Gottlieb, MD, has said are more clearly described “rules of the road.”

More than 351 U.S. businesses were engaging in direct-to-consumer marketing of stem cell interventions offered at 570 clinics in 2015-16, according to an analysis by Paul Knoepler, Ph.D., a stem cell researcher at the University of California, Davis, School of Medicine, and Leigh G. Turner, Ph.D., a bioethicist at the University of Minnesota (Cell Stem Cell 2016;19(2):154-57).

About 4 of 5 of these companies were marketing autologous cell-based interventions, and of these, 61% were advertising adipose-derived interventions (with some companies using the term “stromal vascular fraction” or “SVF”), and 48% were advertising procedures using bone-marrow derived stem cells. The other estimated 1 in 5 businesses advertised allogenic stem cell interventions sourced from amniotic material (17%), placental tissue (3.4%), and umbilical cords (0.6%). Some clinics focus on particular specialties, such as orthopedics, sports medicine and pain management, but others advertise stem cell interventions for a host of disorders, including MS.

The stem cell therapy marketplace has emerged rapidly, likely encouraged by limited FDA oversight, Drs. Knoepler and Turner said in a second, more recent analysis. Between 2009 and 2014, they found, the number of new stem cell businesses with websites at least doubled, on average, every year. And from 2014-2016, approximately 90-100 new stem cell business websites appeared each year (Regen Med. 2018 Jan;13(1):19-27, doi:10.2217/rme-2017-0115). In the meantime, the FDA issued few warning letters to companies selling unapproved stem cell products, they said.

Actions taken by the FDA most recently, in 2018, include warning letters for promoting purported stem cell products without FDA approval and for “significant deviations from good manufacturing practice requirements,” including some that could lead to microbial contamination. One letter, for instance, warns a company administering body fat-derived stromal vascular faction (“intravenously, by inhalation, or directly into the spinal cord”) that its product “involves more than minimal manipulation of a patient’s adipose tissue.” The SVF is therefore regulated as both a drug and a biological product, and can be used in the development stage only if an IND is in effect, the letter says.

Another letter to a company similarly promoting stromal vascular faction to patients with MS and other conditions addresses the issue of “homologous use” as well, stating that the SVF product “is not intended to perform the same basic function or functions in the recipient as in the donor (e.g. “to provide cushioning and support to the body).”

The FDA has taken stronger actions as well. In complaints filed in federal court in May, for instance, the FDA sought permanent injunctions to stop two stem cell clinics from marketing products without FDA approval and for violations of good manufacturing requirements.

According to an FDA spokesperson, the Agency is currently exercising “enforcement discretion for certain products” with respect to premarket review, and will continue to do so until 36 months have passed since issuance of the key guidance document governing stem cell and other cellular- and tissue-based products. This discretion does not include stem cell products “that pose a potential significant safety concern,” he said.

“Going forward,” the Agency spokesperson added, “the FDA will apply a risk-based approach to enforcement, taking into account how products are being administered as well as the diseases and conditions for which they are being used.”

Bruce F. Bebo, PhD, executive vice president for research at the National Multiple Sclerosis Society, said that prior to 2017 “there was a lot of uncertainty as to what was legal and what wasn’t.” The FDA has “clarified things a great deal…and now enforcing the new guidance is a work in progress.”

The MS Society’s webpage, “Stem Cell Clinics—Questions to Ask,” urges caution and asks patients who are thinking about stem cell therapy to carefully evaluate potential adverse effects as well as the clinic’s procedures for managing any complications that may arise. It also includes a list of red flags, such as the lack of research in peer-reviewed journals to back up claims of benefit and the marketing of stem cell treatments for many different conditions (). In addition to the safety of procedures themselves, it says, experts are concerned about potential graft-versus-host disease, the formation of abnormal tissue or cancer, and other long-term consequences.

Underemphasizing risk and exaggerating efficacy is common in stem cell clinic marketing and is compounded by medical crowdfunding campaigns that are launched to finance the treatments, according to the University of Minnesota’s Dr. Turner. He and two colleagues in Canada used the list of 351 stem cell businesses identified in earlier research and found 408 crowdfunding campaigns on GoFundMe and YouCaring that sought donations for interventions advertised by these businesses. Almost 44% of them made statements that were either definitive or certain about the intervention’s efficacy, they wrote in recent research letter in JAMA (JAMA 2018;319:1935-6).

Physicians “should be aware of the potential for crowdfunding campaigns to help spread inaccurate information” and should challenge “problematic DTC marketing messages,” they wrote.