What People Are Talking About: Stem Cell Transplantation for Multiple Sclerosis

Why is this important to me?

You may wonder if stem cells could be used as a therapy to improve MS, especially if your MS is aggressive or responds poorly to disease-modifying therapies.

What is the objective of this study?

For the MS community, stem cells have two interesting qualities. Stem cells: 1. Divide to create new stem cells or 2. Differentiate (mature) into a specific type of cell, say a blood cell or a bone cell. Researchers study different types of stem cells come from many different parts of the body and that can mature into various specific types of cells. Many types of stem cells can be obtained from adults, and ethical concerns are therefore generally not of a concern.

In MS, the immune system functions improperly and attacks and destroys certain components of the brain and spinal cord. At this time, healthcare professionals have no therapies that restore those components of the brain that the immune system has damaged and destroyed. Thus, repairing the damaged brain and/or “resetting” the immune system are important strategies under investigation for treating MS. Stem cells may be helpful for these strategies. Three types of stem cells are being studied:

  • Neural stem cells are capable of increasing cell production in the brain and spinal cord. Neural stem cells are already in the adult brain, or they can be developed from cells in the skin and subsequently introduced in the brain and spinal cord. Researchers had hoped that transplantation of neural stem cells into damaged regions of the brain would lead to repair. This strategy has been somewhat effective when the neural stem cells are delivered directly into the damaged area, but has been ineffective when delivered into the bloodstream. Neural stem cells seem to support the repair potential of cells that were already present at the site of damage to show some signs of repair. They appear to release various molecules that help with repair.
  • Mesenchymal stem cells are usually found in bone marrow and can stimulate reproduction and creation of fat, bone, muscle, and skin cells. Mesenchymal stem cells also release factors that may help cells present at the site of injury repair damage more efficiently. Factors released from mesenchymal stem cells also appear to modulate the immune system in a similar manner as disease-modifying therapies that are currently used to manage MS. Although this activity may be helpful, controlling, delivering, and keeping the mesenchymal stem cells alive remain challenging for researchers.
  • Hematopoietic stem cells are also found in the bone marrow and blood and may be helpful in stimulating development of immune cells. Hematopoietic stem cells can be used to reconstitute a weakened immune system after high-dose immunotherapy to remove the problematic immune cells. Sometimes, high-dose immunotherapy alone without transplantation of hematopoietic stem cells can effectively restore the immune system. These therapies (high-dose immunotherapy alone or high-dose immunotherapy followed by transplantation of hematopoietic stem cells) have lead to improved or stable MS in 73% to 78% of patients. These investigations may help to develop therapies for patients in patients whose MS is not helped by disease-modifying therapies or whose MS is especially aggressive. The problem with hematopoietic stem cell therapy is that it causes serious side effects -- including death -- in many patients. The use of such a risky therapy to treat a disease that is not considered to be fatal (such as MS) creates ethical problems for many investigators. Moreover, hematopoietic stem cell transplantation does not appear to be effective in all individuals with MS, and we do not yet understand the long-term effects of the therapy. Finally, many healthcare professionals have argued that improvements in the effectiveness (and reduction in side effects) of drugs to manage MS make the use of high-dose immunotherapy unnecessary.

These approaches are experimental, costly, carry significant risks, and may be most useful if your MS is aggressive and resistant to standard disease-modifying therapies. More studies are needed before researchers agree that these therapies are safe and effective enough for wider use.

How did the authors study this issue?

The authors reviewed clinical studies addressing the promises and problems of possible stem cell therapy in people with MS.

Original Article

Moving Targets for Hematopoietic Stem Cell Transplantation for Multiple Sclerosis

M. Mateo Paz Soldán, MD, PhD; Brian G. Weinshenker, MD


The following excerpt has been extracted from JAMA Neurology

... HSCs [Hematopoietic Stem Cells] are used to reconstitute the immune system following myeloablation with high-dose immunotherapy (HDIT) rather than for their immunomodulatory or CNS regenerative potential. Although nonmyeloablative HSC transplant has been reported, HDIT is still used in that context, complicating the detection of additional therapeutic benefit of HSCs. As discussed below, HDIT has potent effects on suppressing MS. During the past 2 decades, several hundred patients withMS have received HDIT with subsequent HSC transplant, as previously reviewed.5,6 Patients received treatment most often in small, open-label, phase 1 and 2 trials. Patients with progressive MS showed less-favorable outcomes compared with those with relapsing MS, consistent with the nowaccepted view that progressive MS is degenerative rather than inflammatory. Intermediate-intensity chemotherapy regimens (most commonly carmustine, etoposide, cytosine arabinoside, and melphalan in combination with polyclonal rabbit antithymocyte globulin) have efficacy comparable to that of earlier high-intensity regimens.5,6 Treatment-related mortality has decreased from 5% to 6% to approximately 1.5%, in part because of the decreased intensity of contemporary chemotherapy-conditioning regimens. Progression-free survival has ranged from less than 40% to nearly 80% at 2 to 3 years. The longer the follow-up, the lower the chances of the disease remaining progression free.5,6

High-dose immunotherapy also has been studied without subsequent HSC transplant (HCT). Mitoxantrone hydrochloride was effective in reducing disability accumulation in rapidly worsening relapsing and early secondary progressive MS, but the toxic effects of the drug limit its use.7 The differential susceptibility to cyclophosphamide of hematopoietic progenitors compared with committed lymphoid cells allows for semiselective ablation of differentiated cells, sparing progenitors and enabling rapid reconstitution of the immune system without HCT. A few studies8,9 of high-dose cyclophosphamide reported efficacy similar to that achieved in HSC trials, showingmarked immunosuppression in all patients at the time of therapy and, at 2 years of follow-up, sustained improvement or stability of disease in 73% to 78% of patients.

In this issue of JAMA Neurology, Nash et al10 report the 3-year planned interim results of a prospective study of autologous HCT designed to reconstitute the immune system in patients with MS. The sample included patients with Kurtzke Expanded Disability Status Scale (EDSS) scores of 3.0 to 5.5 with evidence of clinical relapse activity (≥2 attacks of moderate or greater severity in the prior 2months). Disease-modifying treatment had failed in these patients at some time within the 4 years preceding enrollment; the median number of nontransplant drugs that had failed was 3. At 3 years, Kaplan-Meier survival estimates indicated that 78.4% of 24 patients who received a transplant were free of any events in the composite end point, including death and evidence of neurologic deterioration orMS disease activity, based either on clinical ormagnetic resonance imaging (MRI) findings at 3 years. Although the authors report comprehensive 3-year results, the proportion of treatment failures increased over time; at 4 years, 68.6% of the patients satisfied the efficacy end point. One patient experienced an MS attack during filgrastim-facilitated engraftment, apparently owing to nonadherence to protocolmandated prednisone prophylaxis. One patient died of lateMS progression and another of asthma. There were 130 grade 3 and 94 grade 4 toxic events,most ofwhichwere expected, but there were some unexpected grade 3 and 4 events, including an instance of respiratory failure. Although there were no MRIdetected events at 3 years, there were 3 late (following 3 years of therapy) MRI events.

This study and another phase 2 single-arm study11 leave little doubt that high-dose immunotherapy is able to substantially suppress inflammatory disease activity in patients with MS who have active disease in the short term. There is some evidence for long-term suppression of MS. Lessons have been learned about how treatment-related morbidity and mortality may be reduced. However, deaths have occurred, even in small studies, and aggressive regimens have resulted in lymphomas associated with Epstein-Barr virus. Furthermore, even when well executed and using polyclonal rabbit antithymocyte globulin to ensure the adequacy of immune depletion, HCT is not curative for all patients and the long-term benefits of treatment are still poorly characterized. Although the mortality rate associated with HCT is low, any deaths attributable to treatment are difficult to accept in MS considering the variability in natural history and its low mortality rate.

With a changing and improving ability to completely suppress any detectable disease activity using standard clinical and MRI measures in MS, the role of HDIT with or without HCT is debatable. A recent metric reported in MS clinical trials is no evidence of disease activity, 12 which is pragmatically defined by a lack of clinical and conventional MRI evidence of disease activity; in the Natalizumab Safety and Efficacy in RelapsingRemitting Multiple Sclerosis clinical trial,13 natalizumab achieved no evidence of disease activity in 37% of the patients at 2 years, which is 5.3-fold better than placebo; in the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis clinical trial,14,15 fingolimod achieved no evidence of disease activity in 31% of the patients at 2 years, which is 4.1-fold better than placebo. Although these rates are not as good as those reported by Nash et al10 and not in a population in which other treatments may have failed, these impressive rates of short-term efficacy with approved treatments lead one to question the value of the added risk and expense of HCT. As noted above, HDIT alone may yield comparable results.

The HCT research community has developed a position paper regarding how the issues regarding therapy might be addressed.6 The authors offer 2 options: (1) open-label registry after a specified sequence of treatment escalation and definition of treatment failure end points and (2) randomization after failure of conventional treatment is determined. The comparator would be the best-available approved therapy, which may vary from country to country and is a “moving target.” Patients and physicians should expect that aggressive and expensive therapy, such as HDIT followed by HCT, should perform better than any alternative treatment and should provide an accepted minimum level of certainty for both complete and sustained suppression of inflammatory disease activity. Nash et al10 show evidence of prolonged depletion of memory CD4+ cells, depletion of CD4+ - dominant T-cell receptor clones, and evidence of “immune reset”; however, clinical or radiologic evidence of relapse trumps immunologic evidence of immune reset, and this study raises concern that those end points have not been adequately achieved. The jury is still out regarding the appropriateness and indications of HCT for MS.



Author Affiliations: Department of Neurology, University of Utah, Salt Lake City (Paz Soldán); Department of Neurology, Mayo Clinic, Rochester, Minnesota (Weinshenker). Corresponding Author: Brian G. Weinshenker, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (weinb@mayo.edu). Published Online: December 29, 2014. doi:10.1001/jamaneurol.2014.3831. Conflict of Interest Disclosures: Dr Weinshenker serves on data safety monitoring boards for Biogen Idec, Mitsubishi Pharmaceuticals, and Novartis Pharmaceuticals and on an adjudication panel for Medimmune Pharmaceuticals; serves on the editorial boards of Neurology, Canadian Journal of Neurological Sciences, and the Turkish Journal of Neurology; receives license royalties from RSR Ltd for marketing of kits for the detection of AQP4 antibodies as a diagnostic aid for neuromyelitis optica; has received consulting fees from Asahi Kasei Medical Company, CHORD Pharmaceuticals, Elan, GlaxoSmithKline, Novartis Pharmaceuticals, and Ono Pharmaceuticals; and receives research support from the Guthy-Jackson Charitable Foundation. No other disclosures were reported.



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