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Paper Published on Recommendations for Speeding Research on Cell-Based Therapies for MS

July 24, 2017

EXECUTIVE SUMMARY
  • More than 70 experts convened in Lisbon, Portugal in November 2015 for an International Conference on Cell-Based Therapy for Multiple Sclerosis.
  • “Cell-based therapy” here refers to the transplantation, delivery or stimulation of various cell types for treating MS. Cell-based therapy is being explored in MS both for turning down damaging immune responses and for promoting nervous system repair.
  • Conference organizers have now published a paper in the journal Brain (Published online 21 July 2017, and available as open-access) that summarizes results of cell therapy studies and makes recommendations to accelerate the development of cell-based treatment solutions for people with MS.
  • The conference was held under the auspices of the International Advisory Committee on Clinical Trials in MS – jointly sponsored by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), with additional financial support from the Americas Committee for Treatment and Research in MS (ACTRIMS) and the Multiple Sclerosis International Federation (MSIF).
  • The paper reviews progress related to specific cell types, including autologous HSCT (hematopoietic stem cell transplantation using cells derived from the person’s own bone marrow or blood), mesenchymal stem cells (derived from many different adult tissues), and oligodendrocyte precursor cells (derived from multiple sources), and makes specific recommendations about next steps for each.
  • Controlled clinical trials were deemed the optimal way to provide answers about which types of cells, which route of delivery, and which types and stages of disease, would be the most promising approach for treating MS. 
Background: Over the last several years, progress has been made in innovative research related to the potential of many types of stem cells, both for reducing MS disease activity and for repairing damage to the nervous system. With the urgent need for more effective treatments that can stop all forms of MS, as well as therapies that can reverse disabilities, the potential of all types of cell-based therapies is being explored. “Cell-based therapy” here refers to the transplantation, delivery or stimulation of various cell types for treating MS.
 
To help accelerate and coordinate this work on a global scale, an International Conference on Cell-Based Therapy for Multiple Sclerosis was convened in November 2015 in Lisbon, Portugal. The conference was held under the auspices of the International Advisory Committee on Clinical Trials in MS – a group jointly sponsored by the National MS Society and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), with additional support from the Americas Committee for Treatment and Research in MS (ACTRIMS) and the Multiple Sclerosis International Federation (MSIF). Conference Chairs were Jeffrey A. Cohen, MD (Cleveland Clinic, USA, also Chair of the International Advisory Committee on Clinical Trials in MS), Marcelo C. Pasquini, MD, MS (Medical College of Wisconsin, USA) and Neil Scolding, PhD, FRCP (Southmead Hospital Bristol, UK). 
 
More than 70 experts gathered to review progress in the multiple approaches to cell-based therapy – the first conference to focus on all major cell-based therapy possibilities for the treatment of MS.
 
Review Paper Published: A scientific paper was written by the conference organizers, based on the conference presentations as well as a review of published and ongoing studies. The paper is now available in the journal Brain, with open access for all (Published online 21 July 2017). It reviews results of cell therapy studies published to date, the basic biological activity and interactions of various cells, clinical trial results and safety, future trial designs, ethics, and practical considerations such as regulatory issues and scaling up for high-volume production of therapeutic cells. Highlights, as well as details including top research questions and recommendations for various approaches, are summarized below.
 
Autologous Hematopoietic Stem Cell Transplantation (AHSCT) - One type of procedure that has been explored for many years in MS is called “autologous hematopoietic stem cell transplantation,” following ablation (destruction) of the individual’s immune system, commonly known as HSCT or AHSCT. This procedure attempts to “reboot” the immune system in people with MS. Stem cells from an individual’s own bone marrow or blood are withdrawn, captured, stimulated, and stored. Then the immune system is depleted, usually by chemotherapy. The stored stem cells are then reintroduced to the same person, usually by infusion into a vein. The reintroduced stem cells migrate to the bone marrow and over time produce new cells that should eventually repopulate the body with an immune system that is less likely to attack the central nervous system.
 
There is more experience using AHSCT in MS than any other cell therapy approach, and the paper describes published results to date, summarized in Table 1 (page 5). The conference participants suggest:
  • That this approach can be highly effective for people with specific MS characteristics (see next bullet), but it is not clear how it compares in safety or efficacy with other highly effective disease-modifying therapies.
  • That those most likely to benefit are 50 years or younger, have had MS for 5 or fewer years, have active relapsing-remitting MS but are still walking, and whose disease is not adequately treated by available disease-modifying therapies.
  • That a formal phase 3 clinical trial is recommended to be conducted that compares AHSCT to one or more highly effective disease-modifying therapies to fully understand benefits and risks and which individuals might benefit most. (At least one such trial is in planning stages.)
  • That AHSCT may be appropriate for individuals with highly aggressive MS that is not controlled by approved disease-modifying therapies. In those cases where AHSCT is performed outside of a formal controlled clinical trial, it is recommended it should be performed at centers with experience doing the procedure and managing MS, and that safety and effectiveness outcomes be collected and submitted to existing bone marrow transplant registries for future publication.  
Adult Mesenchymal Stem Cells (MSCs) – The paper also discusses other stem cells found in the body, including mesenchymal stem cells. These are adult cells found in several places in the body, including the bone marrow, umbilical cord blood and fat tissue. These cells have, to date, undergone limited testing in clinical trials that aim to reduce immune activity and to augment nervous system repair in MS. With this approach, an individual’s immune cells are not destroyed or replaced. Instead, an individual’s MSCs are isolated from the bone marrow, blood or other tissues, cultured in the lab to increase their purity and numbers, and then re-introduced into the body by intravenous (into the vein) or intrathecal (by spinal tap) injection. MSCs are thought most likely to work by encouraging the body’s natural repair mechanisms.
 
The paper describes technical issues related to the source, expansion and preservation of cells, and results of small clinical studies of MSCs in MS (summarized in Table 2, page 10). The authors note that larger, controlled phase 2 studies are underway, and suggest that further trials are warranted. Other suggestions made include:
  • There has not been sufficient testing to determine the best dose, source, culture method, or route of delivery of MSCs.
  • Quality and safety controls are a concern because of the potential for contamination and the potential formation of unwanted tissue and cancers. Long-term monitoring for potential adverse effects is important.
Cell Therapy for Myelin Repair - Another approach, which hasn’t yet been formally tested in people with MS, focuses on repairing nervous system damage with stem cells that may replace damaged cells (oligodendrocytes) that make myelin. Myelin is the protective coating on nerve wires which is damaged during MS. Stem cells called “oligodendrocyte progenitor cells” (OPCs) reside in the brain and can conduct natural repair to myelin in response to injury. These cells have been grown and expanded in lab dishes as a potential source for transplantation. Another cell source being explored involves using an individual’s own cells from skin or other tissues, which are reprogrammed to turn them into stem cells. These cells are called “induced pluripotent stem cells” or iPSCs. It’s possible such cells would not be rejected by the person’s immune system after transplantation. (Read more about other research to repair the damage in MS.)
 
The paper describes a phase 1 clinical trial planned by the New York State Consortium for Cell Therapy to assess the safety and feasibility of injecting OPCs into multiple locations in the brains of people with secondary progressive MS. Given the relative infancy of this cell therapy approach, the authors note many unresolved issues related to safety, regulations, cell sources and route of administration, dosing, and cell production, and also the need to understand the characteristics of people who might benefit. These are outlined in Box 4 (p. 15).
 
Promoting Clinical Trials of Cell Therapy – The paper outlines questions that are common to all types of cell therapy for MS, including:
  • what are the best doses, routes and frequency of cell delivery;
  • how to track transplanted cells within the body;
  • how to determine if cell therapy is working;
  • optimal clinical trial designs and study populations for each cell type;
  • the role of cell therapy in relation to the use of approved disease-modifying therapies;
  • ethical challenges, including the issue of patient-funded studies and the problems of medical tourism and unregulated stem cell clinics; and
  • how to monitor for safety.
A past roadblock has been that clinicians often use different treatment protocols, different stem cell types and preparation, and other technical issues, making it hard to compare results. The authors recommend that stem cell therapy be tested by networks of researchers using standardized protocols so that data collection and analysis can be centralized. Several such networks exist or are being planned.
 
Controlled clinical trials were deemed an optimal way to provide answers about which types of cells, which route of delivery, and which types and stages of disease, would be the most promising approach for treating MS.  

Read the open-access paper in Brain
Read more about stem cells and MS
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About Multiple Sclerosis

Multiple sclerosis is an unpredictable, often disabling disease of the central nervous system that disrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are leading to better understanding and moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.3 million people worldwide.

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