A conversation with Sean Savitz, MD, Frank M. Yatsu M.D. Chair in Neurology, Institute for Stroke and Cerebrovascular Disease, The University of Texas Health Science Center at Houston, on stem cell therapies for acute ischemic stroke.
Interviewed by Mark R. Etherton, MD, PhD, Assistant in Neurology, Massachusetts General Hospital, Instructor, Harvard Medical School.
They will be discussing the paper “Intravenous Cellular Therapies for Acute Ischemic Stroke,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.
Dr. Etherton: The data from MASTERS-1, as well as the animal studies, suggests a promising, immunomodulatory role for MAPCs in ischemic stroke, as well as for cells derived from other tissue sources. Can you speak to the advantages/disadvantages of MAPCs over other cell types?
Dr. Savitz: There are several advantages that make MAPCs appealing. One is that they have been studied extensively in pre-clinical animal models and now quite a bit in clinical trials, which has resulted in a significant amount of safety data obtained from these rigorously designed trials. So, in designing a therapy for stroke, I am of the opinion that it is important to choose a therapy based around animal studies and solid testing in early stage trials. We are encouraged by the fact that the clinical studies suggest MAPCs are safe in humans, and we already see signals suggesting that, if given in the right time window, the cells are effective to improve outcomes. In this respect, there are few if any other cell types that have gone this far on the continuum from animal studies to an impending phase 3 trial.
The other advantages of MAPCs are that cells are purified from a healthy volunteer and then administered at the bedside. Other cell therapies require obtaining cells from the patient, which is a more involved approach to actually harvest bone marrow on the patient and then purify out the cells of interest. With MAPCs, it is essentially hanging a bag of cells at the bedside. Another advantage is these cells are smaller than mesenchymal stem cells, which may be a distinct advantage as the smaller size may mean less filtering as they pass through the lungs. As a large part of the immune mediating processes is thought to occur in the spleen, if more cells can get to the target of interest, that is a unique advantage. Lastly, there is some animal data that suggest MAPCs may perform better than other cell types for ischemic stroke.
Dr. Etherton: The current evidence suggests that MAPCs administration works, in part, through reduction in splenic atrophy post-stroke. In splenectomized animals, however, MAPC administration also reduces tissue injury. What do you think the mechanism is for this observation? Is it still regulation of cytokine release in another tissue bed or something else?
Dr. Savitz: We were intrigued by the results. It indicates the MAPCs are not just exerting all their effects in the spleen and there are other targets. We are interested in teasing out those mechanisms. The essential question is, where else are the cells having an effect? Other cell types have been shown to influence the lung and bloodstream, which are areas we are starting to look at in the subacute timeframe post-stroke. This observation also suggests the effects of MAPCs very well could be multifactorial. We see a lot of changes occurring in the brain; the question is, how much of those beneficial results are a direct effect of the spleen? There is a broad array of repair mechanisms that are upregulated in the brain in animals treated with MAPCs, including gene expression patterns and signal processes. The question is, how much of those processes are upregulated because the cells are affecting the spleen first?
Dr. Etherton: What are your thoughts on the studies investigating different routes of administration of cell therapies, and do you think the cells are working through the same mechanisms or different depending on location (e.g. stereotaxic intraparenchymal infusion versus intravenous)?
Dr. Savitz: I think it really depends on the intention of the study, as I think it is very different for each delivery mechanism. In the case of intravenous cellular therapies, what we’ve come to learn is that there is an advantage to administering via an intravenous route, which has the widest clinical applicability, to modulate the systemic inflammatory response to downregulate the detrimental aspects and upregulate the beneficial elements of the inflammatory response. Conversely, I think the intention of direct delivery is that you want to deliver the stem cells to the brain. With the intravenous administration, what we’ve learned is that very few of these cells actually enter the brain. So, as you can see, straight off the bat the intentions are very different between intravenous administration and direct delivery (stereotaxic injection). If the goal is for CNS penetration, intravenous administration may not be the best opportunity based on what we know happens to these cells. The chronic stroke studies are doing direct delivery because they want to have a direct impact on the brain that somehow promotes recovery in the chronic stages of stroke with a local effect in the area adjacent to the injury to change the micro-environment. The intra-arterial route also has a lot of attractive features, but it’s really for the purpose of saying we want to deliver something that gets into the brain close to the area of damage. An example may be directly wanting to directly target cells into the peri-injured area and modulate the local CNS environment.
Dr. Etherton: What are your thoughts on the timing of administration of intravenous cell therapies, and do you think there is a critical window for administration or simply the earlier the better? In MASTERS-1, as you know, the effect of MAPC administration on rates of excellent outcome at 90 days appeared to be greater in the subgroup that received cells 24–36h from stroke onset compared to 24–48h.
Dr. Savitz: I don’t think we know what the earliest time point is for benefit. My hypothesis is that probably there is such a thing as too early being too early, and it may not work in the hyper-acute stages. I think it’s about immune targets being available at the right time. What we’ve learned from MASTERS-1 and the animal studies is there is a time window that you have to impact the inflammatory response, and then after that it is probably too late. It’s all about targets, just like in the acute reperfusion trials where thrombectomy works when we have confirmed LVO. It may be the same principles here that we have to find the right time window when inflammatory targets emerge after symptom onset and then disappear.
Dr. Etherton: The outcome data from MASTERS-1 is intriguing in that a single IV administration of MAPCs 24–48h post-stroke increased the rates of patients with excellent outcomes at 1 year but not 90 days. Why do you think there is this late separation with MAPC administration? Was it simply a result of the power of the Phase I/II trial or something else?
Dr. Savitz: I think it speaks to something really interesting. It takes time for the brain to undergo repair, and that 90 days may not be the optimal timeframe to look for the full effects of the treatment. We think about repair and plasticity, the studies indicate these are processes that take time to become operational, and they may be ongoing for a long time beyond 3 months. The 3-month timeframe was chosen for the acute stroke reperfusion trials, but in the case of cellular therapies for ischemic stroke, this is an entirely different approach that may take a lot longer to show the full effects. The brain is changing and remodeling over time. It takes time for the brain to remodel and change and be in a more pro-regenerative process, and I think this is what we are seeing with the results of MASTERS-1 at 3 months and 1 year.
Dr. Etherton: What are your thoughts on the applicability of MAPCs to other neurological injuries such as hemorrhagic stroke?
Dr. Savitz: I do believe there may be a role for stem cell therapies in other acute neurological disorders. The animal studies very much support that there may be a convergent mechanism for stem cell therapies in various different acute neurological disorders (e.g. stroke, spinal cord injury, traumatic brain injury). In traumatic brain injury and intracerebral hemorrhage, for example, there are data that the spleen is changing size. Regarding MAPCs, in particular, investigators led by Dr. Mays at Athersys and many of their academic collaborators are showing in pre-clinical studies benefits of MAPCs through direct effects on the spleen in TBI, spinal cord injury, and hypoxic-ischemic encephalopathy. It very well may be that the approach we are looking at in acute ischemic stroke may work in similar ways in other acute neurological injuries I do hope that we will see more clinical trials get off the ground looking at the role of MAPCs in other acute neurological injuries.
Dr. Etherton: Thank you very much.