In patients with MS, the immune system abnormally attacks the central nervous system, causing damage to the nerve cells and their protective myelin sheath. The body has mechanisms that attempt to repair this damage; however, in MS, the repair cannot keep pace with the ongoing damage.
The Phase 1 trial involves harvesting a patient's mesenchymal stem cells (MSCs), which are primitive cells in the bone marrow, culturing them in a laboratory, and then injecting the MSCs intravenously back into the patient to see if the procedure is safe, decreases disease activity, and leads to improved repair.
The research team is headed up by Jeffrey Cohen, MD, of the Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research, and is funded by a $2.75 million, four-year grant from the United States Department of Defense and a $1 million grant from the National Institutes of Health. Dr. Cohen is Director of the Mellen Center's Experimental Therapeutics Program and Professor of Medicine (Neurology) in the Cleveland Clinic Lerner College of Medicine of the Case Western Reserve University School of Medicine. He has taken a lead role in a large number of MS clinical trials, including a Phase 3 trial that led to the recent approval of the first oral therapy for MS.
"Currently, there are eight medications approved to treat MS. They slow the disease but none of them reverses it. The hope is that mesenchymal stem cells will lessen ongoing damage caused by MS and promote repair," said Dr. Cohen. "We're taking a cautious approach, carefully monitoring for any unexpected side effects, as we look to see if MSC have the abilities that we anticipate."
MSCs have a wide range of effects that decrease the activity of immune cells while encouraging tissue repair, both of which may be beneficial in MS. In addition, in numerous laboratory studies, MSCs were able to migrate from the blood into areas of inflammation or injury in the nervous system and reduce damage probably by creating a tissue environment that encourages the body's intrinsic repair processes.
Study participants will be monitored very closely for six months after they receive the MSC transplantation, including physical exams, blood work, and other testing to determine whether the procedure is safe and well-tolerated. The research team will also monitor their disease status through quantitative neurologic exam, vision testing, advanced MRI, and optical coherence tomography of the retina prior to and for six months after MSC administration to evaluate whether the procedure impacts the activity or severity of each participant's MS. Finally, in collaboration with investigators at the Montreal Neurological Institute, the immunologic effects of MSCs will be comprehensively assessed, both in culture and in the patients.
Cleveland is one of only a handful of locations in the country where a research endeavor like this could be conducted because it is home to a "dream team" of clinical and research experts with strong collegial relationships; located less than two miles from each other:
- Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research, part of the Neurological Institute;
- University Hospitals (UH) Seidman Cancer Center Coleman Clinical Research Suite;
- Cellular Therapy Laboratory (CTL) based in the Case Western Reserve University School of Medicine National Center for Regenerative Medicine (NCRM), a multi-institutional program comprised of investigators from Cleveland Clinic, Case Western Reserve University, UH Case Medical Center, Athersys, Inc., and the Ohio State University.
- Baseline testing, including general and neurologic exams, vision testing, MRI, and optical coherence tomography, conducted at Cleveland Clinic's Mellen Center.
- Participants have their bone marrow aspirated from their hip in the Coleman Clinical Research Suite at UH Case Medical Center.
- The stem cells will be culture-expanded in the CTL in the NCRM then frozen.
- Participants then have their stem cells infused in the Mellen Center.
- Follow-up monitoring and testing will be done at the Mellen Center.
This study requires a specialized Class 10,000 cleanroom environment and uniquely qualified personnel because the study subject's marrow cells need to be grown ex vivo (outside of the body) for approximately a month to achieve an adequate number of MSCs. Once the desired dose is obtained, the cells are tested extensively to confirm they are viable and not contaminated to ensure safety, then cryopreserved. At a later date, they are transported to Mellen Center, carefully thawed, and infused intravenously. This type of cell manipulation is performed under the authority of the US Food and Drug Administration and must follow strict procedures, documentation, environmental and equipment monitoring, and quality assurance that is not feasible in a typical research lab.
The bone marrow harvesting is performed by physicians in the Coleman Clinical Research Suite in the UH Seidman Cancer Center (formerly known as the UH Ireland Cancer Center). UH Seidman Cancer Center is widely regarded as a pioneer in the field of hematopoietic (non-embryonic) stem cell transplantation, particularly in the development of MSCs to treat blood cancers. The first in-human trial of MSCs was published in 1995 by researchers from Case Western Reserve University and UH Seidman Cancer Center. Subsequently, UH Seidman Cancer Center conducted the first-in-humans trial of MSCs in autologous hematopoietic cell (blood/marrow) transplant (2000) and the first-in-humans trial of MSCs in allogeneic hematopoietic cell transplant (2005).
Arnold Caplan, professor of biology at Case Western Reserve University who was involved in the first in-human trials of MSCs, and Robert Miller, a professor of neurology and associate dean for research at the Case Western Reserve School of Medicine, laid the groundwork for the current clinical trial. They discovered that in mice that have a form of MS, human MSCs promote healing of damage and protect against an autoimmune response. Drs. Caplan and Miller are members of the clinical trial's advisory committee.
Dr. Stanton Gerson, M.D., director of the UH Seidman Cancer Center and director of the National Center for Regenerative Medicine (NCRM), said, "This trial in MS is one of the most innovative trials of MSCs as it truly investigates both the clinical aspects as well as the science of what these cells do and how they may confer therapeutic benefit to recipients."
Dr. Gerson also added, "This trial is real joint venture. We have the experience of collecting, expanding, and infusing MSCs. Cleveland Clinic has extensive expertise in MS clinical trials using ultra-sophisticated imaging and other techniques. All three centers (Case Western Reserve, UH Case Medical Center, and Cleveland Clinic) have great basic neurologic science to understand what is happening with the cells and the patients."
The Phase 1 study, which will take two to three years to complete, will involve 24 patients with relapsing-remitting or progressive MS who have moderate to severe disability. If this trial demonstrates that MSC transplantation is safe, future studies will more definitively assess the efficacy of this therapy in MS. The study has already enrolled 4 patients, and the team expects to begin to report their initial findings over the next 1-2 years.