Could you explain the stem cell procedure that you’re testing?
There are currently eleven medications approved to treat multiple sclerosis and several more around the corner. The available medications are all useful in relapsing MS – an inflammatory phase in the disease – but there is a big need to find treatments for progressive MS. We think this will require different strategies, such as neuroprotective treatment strategies or repair-promoting strategies, which has led to a lot of interest in cell-based therapies.
There are many types of stem cells. The type we are testing are called mesenchymal stem cells. These cells are present in many tissues of the body, and have been studied fairly extensively, which is why we chose to focus our research in this area. In our study, the stem cells were extracted from the patients’ bone marrow, then the cells were grown in the lab to purify them and increase their numbers. They were then frozen and at the time of treatment they were thawed and injected intravenously back into the patients.
Was there a specific reason you chose to look at mesenchymal stem cells?
There has been a lot of research on mesenchymal stem cells in a variety of animal models, a variety of laboratory studies, and also in other conditions, which provides valuable background information. They also have several properties that make them of interest for treating MS. First, they appear to have neuroprotective or tissue-protective properties. They also appear to encourage intrinsic (or natural) repair mechanisms within the tissue. They have some immune-modulating properties – even though that wasn’t our prime motivation, it was an added benefit. Finally, they appear to be able to migrate from the blood into tissues that are inflamed or damaged, which allows for a much more convenient way of administering the cells. We don’t have to inject them directly into the nervous system – we believe that we can introduce them intravenously or via a spinal tap and they will find their own way to the areas of damage.
What are you expecting to learn from this study?
The study we just completed was what’s called a phase I study. It focused on feasibility and safety of the procedure. The results were very encouraging; we didn’t encounter any practical issues or safety concerns, and very few side effects. We also took a preliminary look at benefit – both reported by patients themselves and clinical measures – and a range of advanced imaging and immunologic techniques. Not because we thought we’d get a definitive answer on whether this approach was effective, but rather for preliminary indications of whether the procedure was helpful, how much it might be helpful, how long the benefit might last, and to practice specific assessments in preparation for what we hope will be a larger study that looks more directly at benefit.
You said the study is complete, but could you talk a little bit about who was included in the trial?
This was a relatively small study. We enrolled 24 people with MS. Approximately half had relapsing-remitting MS and half had more severe secondary-progressive MS. We wanted to assess a wide range of people to see first of all if there was benefit in one stage of the disease or another, and more importantly to see if there was any indication of safety concerns in one stage or the other.
One concern we had when we started this study was that there have been experimental treatments that seemed like a good idea for MS but in fact didn’t work and made the disease more active. There are biological properties in these cells that make this a plausible concern. What we were looking for was any indication that these cells made the disease more active after we administered the cells. Thankfully, we didn’t see any evidence of that.
People in the study were enrolled and then underwent a bone marrow extraction. It took four to five weeks for the cells to grow in culture. Over that time we did a variety of assessments of disease status After that we infused the cells back into the participants, and we monitored them for the following six months, looking for evidence of any side effects or complications, and any indication of improvement.
Were there any particular types of MS or people who were excluded from the trial?
Because this was a preliminary safety study, people on certain medications were excluded. We excluded people taking potent immune-suppressing drugs, because we wanted to make sure that if someone had a complication, we knew whether it was due to the cell therapy or the medication. There is also concern that some disease-modifying therapies may interfere with the ability of these cells to migrate or to repair damage. For example, Tysabri, one of the approved medications, works by blocking immune cells migrating into the nervous system and we think it may do the same to these stem cells.
There were also restrictions on other medical conditions and age. It was an intense study in terms of the number of visits, so that restricted it to people who could get to Cleveland to participate. Since we encountered very few safety issues, the hope is that the next study can be more relaxed in terms of the eligibility criteria and the number of visits required.
Do you know when you’ll have final results from the trial?
We are finishing up tabulating the results now. They will be presented at the upcoming joint American and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting in Boston in September, and several publications are also in preparation. We hope to have the results published this year.
Is there is anything else you’d like to share about the trial?
We were pleased that the study went so smoothly, but it was apparent that there were a lot of issues related to stem cells, includinguncertainties of how best to grow them, where to isolate and administer them, and the optimal dose.These are all issues we are discussing as we plan the next study.
Is there any advice or caution you would offer people as they consider stem cell transplantation, either through a clinical trial or a clinic not associated with a trial.
I share in the excitement and interest in cell-based treatment for MS – it shows a lot of promise. I also appreciate that people are anxious to pursue those therapies now. But it is also very clear to me that there are a lot of unknowns in cell-based therapies. We don’t know which cell type is the most appropriate to use, where to isolate the cells from, how best to grow them in culture. We also don’t yet know the correct dose or best route of administration.
At this point I think it is premature to pursue cell-based therapies outside of a carefully conducted, formal clinical trial. It is premature to pay large sums of money and travel to other countries to get these therapies. I have concerns that what is being done in many clinics around the world isn’t clear, and that we aren’t ready to pursue these therapies outside of clinical trials.
If someone were to consider entering a trial how would they know where to look or what questions to ask to ensure that it is a carefully administered trial?
Clinicaltrials.gov and the National MS Society have a listing of ongoing studies; the International Society for Cellular Therapy is a useful source of information on cell-based therapies.
General questions people should ask are: What is the rationale for this particular cell therapy? What kind of experience do the investigators have? What is the plan to monitor for safety? I think a red flag would be if the plan is to have the cells administered and send you home with no follow up.
Do you anticipate that the next trial you conduct will be conducted solely in Cleveland again?
That is something we are wrestling with. On one hand we’d like to open this up to people that live further away. However, growing the cells is tricky so it’d be very hard to manufacture them at other institutions. We are considering a compromise in which cells are isolated, grown and administered here, but some of the other follow up could be done elsewhere. In which case, it would require one to two trips to Cleveland.
What makes you so excited about research in this area?
It’s an area of big unmet need in MS and other conditions in which there is injury to tissue. And the work that has been done so far has been very promising. I believe cell-based therapies are going to be a big part of medical practice in the future. The particular cells that we studied are the initial endeavor, but there are a number of other more advanced cell therapies that are being developed. I think there’s a good chance in the future this is going to be how we treat a lot of diseases.
Jeffrey Cohen, MD, has worked at Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research since 1994. Dr. Cohen has a large clinical practice devoted primarily to the care of patients with multiple sclerosis and related disorders. In addition, he is Director of the Experimental Therapeutics Program and has been involved in various capacities in a large number of clinical trials developing new therapies for multiple sclerosis.
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