Stanford Medcast Episode: Hot Topics Mini-Series - Stem Cell Therapy in Multiple Sclerosis

Ruth Adewuya, MD: Hello. You are listening to Stanford Medcast, Stanford's CMEs podcast, where we bring you insights from the world's leading physicians and scientists.

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I am your host, Dr Ruth Adewuya. This episode is part of our Hot Topics Mini-Series, and is supported in part by an unrestricted educational grant from Novartis Pharmaceutical Corporation.

In episode 40, I chatted with Dr Lauren Steinman on the role of the Epstein-Barr virus in MS: its impact and potential opportunities for treatment. In the last episode, I had a great discussion with Dr Manuel Bavahn on what we know about the gut microbiota as a cause or consequence of MS.

In this episode, I continue the conversation on multiple sclerosis with Dr Jeffrey Dunn, with a focus on stem cell therapy in multiple sclerosis. Dr Dunn is the Lily Sarafan Director of Neuroimmunology, Clinical Professor and Chief of Neuroimmunology at Stanford University Healthcare and the Stanford University School of Medicine.

He specializes in the diagnosis, treatment, and research of multiple sclerosis, and is a principal investigator in the BEAT-MS clinical trial, which will assess the benefit of autologous hematopoietic stem cell transplantation versus the best alternative therapy for relapsing MS.

Dr Dunn, thanks for chatting with me today.

Jeffrey Dunn, MD: Thanks for the opportunity. This is really great to get the word out and to increase awareness about the possibility of stem cell therapeutics for MS.

Adewuya: Let's start with a few differentiations and definitions, since we know that there are different kinds of stem cells. Can you set the stage for us? Especially which type is relevant to the discussion on multiple sclerosis?

Dunn: Yeah. Stem cells was a very general term. It tends to be bandied about a bunch, but there's actually multiple different subtypes of stem cells.

In general, stem cells have in common this idea that they're very undifferentiated. Almost like the infants of the cells in the human body, where they're potentially capable of almost anything, which is what gives them great promise. But by themselves, typically are not really capable of doing anything.

As far as MS goes, I think there are generally regarded about five different subtypes of these stem cells. And they do have a differential relevance with respect to MS. The most common, and what I think people have researched the most and that we know most about, are the hematopoietic stem cells, typically within the marrow. And we'll talk about that, I think, more in just a sec.

But just to give the high altitude: there's hematopoietic stem cells that are in the marrow. There are mesenchymal stem cells that can be derived from multiple different tissues, including marrow and even adipose tissue. Then also neuro stem cells that are specific to the central nervous system. Human embryonic stem cells that are embryonically derived. And then you can even induce pluripotent stem cells from other tissues.

So I think there are five different kinds of stem cells, and they have different implications as far as MS and different potential advantages in the treatment of MS.

Adewuya: Do we have any FDA-approved stem cell therapies for MS?

Dunn: We do not. That's important to know, because as exciting and as much potential as stem cells offer, certainly patients should know and physicians should know that nothing has been proven.

There are trials underway, which we'll discuss, I'm sure, just in a moment. But as of now, stem cell therapy, whether it be autologous hematopoietic stem cell transplantation, or mesenchymal stem cell infusions, or the other modalities I mentioned, are not FDA-approved for the treatment of MS.

Adewuya: Thank you for starting the conversation with that disclaimer, I think that's really important to note. As we dive into the conversation of stem cell therapy in MS, what are some of the ways that we are considering using stem cell therapy in MS?

Dunn: Great question. One attribute of MS: 85% of the 1 million men and women who live with MS in the United States will have their disease start with a relapsing form, in which they get attacks, and then recoveries.

A single attack, of course, can be deeply, profoundly frightening to the patient. So an attack, even if it does recover, is a big deal in its own right. Not all cases of MS have relapses, as the clinicians listening in will know. But about 85% of MS will begin with relapses.

So the thought is that something happens in the human body that induces this autoimmune attack in which the immune system comes at one's own tissues, including the central nervous system. And that can occur on a repeated basis.

With each attack, of course, there's the risk of injury and disruption of nerve signaling. And that can lead to any of a number of myriad symptoms we associate with multiple sclerosis, ranging from numbness to weakness, to imbalance, to fatigue, to decreased cognition, visual change, and many other symptoms as well.

There has been a theory that perhaps something happens to imprint upon the monitoring system or the immune system that predisposes to this autoimmunity. So the type of stem cell therapy that's been most looked at is the autologous hematopoietic stem cell transplantation. The potential indication and value of that is for relapsing cases of MS. I'd like to get into the history of that a little bit about why that's the case.

But the thought and the hope there is that such a therapy might substantially decrease relapses. And if we can decrease relapses, the hope is that we can keep people with MS living healthier, more robust lives with less impairment and less limitation over the course of many years.

Adewuya: I would love to hear the history that you alluded to. How did we get to this point?

Dunn: A lot of the early observations actually came out of the Fred Hutch Cancer Center in Seattle, where I'm from. And what was found was as they were using stem cell therapies, the stem cell transplant treatment, for hematologic malignancies like leukemias ... This goes back more than 20 years now ... There was note made that people who had autoimmune diseases at the same time were actually getting better.

It looked like their autoimmune diseases were improving in association with stem cell transplant therapy. So the doctors there, including Dr Georges and my colleague, Dr Jim Bowen, astutely realized that this potentially could be really helpful for multiple sclerosis. So they looked at and created a protocol by which this autologous hematopoietic stem cell transplantation could be used in patients with MS.

Some years ago, they published the retrospective analysis of the experience they had with MS patients when they were treated with this modality between 1995 and 2006. And I think their results are really telling; here's what they found.

They assessed for progression-free survival at a five-year mark. All right, that means if a patient has MS and is having attacks and they receive this transplant therapy, how many of those patients succeed to the point where they have no attacks over five years after treatment? That's obviously a really valid thing to look at.

Unfortunately, in that period, the early period, when this was just starting to be used clinically for MS, only 46% were progression free at five years: less than half. That was a bit disappointing on its face.

The investigators looked into this a little bit more. And what they found was that patients who had had secondary progressive or primary progressive, which is a subtype of MS where they were getting worse in the absence of relapses, generally did not do well, necessarily. Only 33% of patients who had that type of MS benefited from this treatment. But patients who had relapsing MS, where they were still in the inflammatory phase of their disease, had a 73% response by this metric.

So the analysis of that data suggested that maybe this autologous hematopoietic stem cell transplantation is a therapy that's most apt and most applicable to people who are having active relapses. And that theory has since been validated by other studies. Sorry to give a long answer there, but-

Adewuya: No, I think it's helpful to understand how clinicians and how researchers arrive to the conclusions that they get to.

You mentioned earlier that the exciting thing about stem cell therapy is the idea that it could potentially reduce relapses. Can you articulate the gap or the limitation of what we know of the best available disease-modifying treatments that you think stem cell therapy could help address?

Dunn: If we're talking about just the autologous hematopoietic stem cell therapy, it looks as if this type that really aggressive cases. This does happen where patients who, when they developed MS, have really bad attacks or frequent attacks in the early days, leading them from being normal to really having significant impairment as a consequence of those attacks within a matter of months, or even a few years. Even though we have many FDA-approved medications, some of those medications don't necessarily stop severe aggressive disease like that.

And so the hope might be that this therapy, which is obviously much more robust; it gets right into the marrow. It takes the patient's immune system, literally ablates it down to zero, and then rebuilds it from scratch.

When I talk to patients, I use an analogy, which I'm sure hematologists will not find too artful. But I say, "Look, if you have a front yard and it's full of weeds and you haven't been able to get rid of the weeds, what you do is you just take the yard right down to its dirt, and then you reseed with just grass seed only. Then that brings up a beautiful grassy lawn, and all the weeds are gone. It's a much better approach than taking weeds out one by one."

That's a very limited analogy, obviously, but that's the dynamic of this transplant therapy. The thought is that at the level of marrow, there's been an adjustment or maybe a maladjustment in the immune system, which has predisposed the person with MS to have an autoimmune tendency.

If we can essentially annihilate that, take it all the way down to like starting anew, and then reseed with the patient's own cells, that we can build back the immune system the way it was initially meant to be. And that might decrease the autoimmune reaction. That's the theory behind this. So you can see it speaks to really aggressive disease.

Adewuya: Can we switch gears to talk about the mechanisms of action of stem cell therapy? Could you clarify what those mechanisms are? Are they directly repairing damaged nerve cells, or are they rebooting the immune system? Or as you mentioned, wiping the grass and bringing it all the way to dirt and then seeding again?

Dunn: Yeah. The short answer's going to be, we don't really know, though. That's the tricky part about this. Again, with autologous hematopoietic stem cell therapy, the initial theory what engendered, I think, so much interest in this potential treatment modality, was the idea that the immune system in the MS patient was altered and could be rebooted. It could be taken down to its studs and rebuilt in a healthy, balanced way with restored immunomodulation and proper balance of the on signals and off signals of the immune system.

But how do you prove that that's the case? There are some authors who have done these studies more recently, who have said maybe the benefit that we're seeing in terms of decreased relapse rate has to do with immunosuppression. Because the very treatment that is required to do this transplant procedure requires substantial immunosuppression, such as with busulfan and cyclophosphamide or cytoxan and antithymocyte globulin, depending on the condition regimen.

Theoretically, this could reset the immune system. Or, the benefit could be derived from anti-inflammatory therapy. There are ongoing clinical trials, and we're going to try to figure this out to really define what the benefits are, who the ideal patient might be ... if this treatment might be better or more effective under some conditions than others, and so on.

I should say too, just to be thorough, for example, with mesenchymal stem cell therapy, which is a different kind, the mechanism of that's completely different. Instead of having an anti-inflammatory effect, mesenchymal stem cells are thought to be beneficial by promoting remyelination by natural honing mechanisms to damaged or inflamed tissue, and promoting oligodendrocyte formation and maybe restoration of the local cells in the local milieu.

Adewuya: My next question was around differentiating the types and the sources of the stem cells and their advantages.

Dunn: So let me just review a little bit, looking at this and the different potentials of stem cells through the eyes of the patient with MS and what they're going through.

For example, the MS patient who has a relapsing form of the disease and is inclined to recurrent attacks where the immune system periodically intermittently recurrentLy disrupts their brain and spinal cord signaling: the way in which we can most help that patient, arguably, is by stopping those relapses to protect their brain and spinal cord.

Not all kinds of stem cell therapy necessarily decrease relapses. But this would be where the autologous hematopoietic stem cell therapy has been shown to be effective. Stemming from the early work from Fred Hutch and those investigators dating back to the mid-'90s, we have evidence that this particular therapy, the transplant therapy with a high conditioning regimen, can decrease relapses and is most effective arguably for the relapsing MS patient.

And it seems to be less effective for the progressive MS patient who either has the progressive form of MS, or has had MS for a number of years, and therefore is losing strength or endurance or stamina, even in the absence of relapses. So the stem cell therapy appears to be indicated for relapsing forms.

While I'm on the subject, let me just mention: you can see there's an immediate complication in that we know that stem cell therapy, by knocking the marrow down, by ablating the patient's immune system, is an aggressive therapy. And yet it seems to be arguably most effective for people that have had early-onset MS who maybe are only some years into their disease.

Do you use aggressive therapy in somebody that's only had MS for a few years? That's one of the central questions we'll have to address in clinical trials to follow. But for the relapsing MS patient, the transplant therapy seems to be what we would want to try to see to develop and better define if that's effective, or if there are certain subtypes where there may be a super response or an especial indication.

Now, there's another challenge that MS patients face, and those that live with it: it's difficult, and it's difficult for the clinicians and my colleagues that care for patients with MS. And that's once they've developed deficits, they live with those deficits, whether it be spasticity or motor weakness or difficulty walking, even in the absence of relapses.

So there's the real impulse to wonder, is there anything that we can do that can help restore the strength of those patients? If they're weak today, can we turn that around in any way? And I think one of the reasons that stem cell therapy has gotten so much attention and so much interest is theoretically, stem cells, because of the way they work, potentially could do that.

So the mesenchymal stem cells that we talked about, which is another subtype, potentially could be derived again from marrow, sometimes even from adipose tissue at other times. Then given even intravenously, for example, where those cells seem to hone in and recognize the damaged areas. And they hold the potential of being able to repair myelin.

In one case, we have a therapy that might decrease relapses. In another case, with the mesenchymal stem cells, we potentially have a therapy that could do some restoration and regeneration. You can see automatically the profound interest that would have in patients that are living with deficits.

Adewuya: Absolutely; really exciting work and high potential there.

We alluded throughout this conversation, we talked to clinical trials that are happening in this space. So I want to switch gears to that, in terms of some of the studies that are happening starting through phase 1, phase 2 and phase 3. But let's start with phase 1 studies on safety. Can you summarize for us some of the major findings of phase 1 studies on safety?

Dunn: Yeah, there are a couple things. With the autologous hematopoietic stem cell therapies, there was a European review that showed that treatment-related complications, with the immunosuppression that was used and the conditioning regimens that were used, that patients undergoing that therapy could experience complications within 100 days of treatment in as many as 7.8% of cases. Which, obviously, is almost one out of 10 patients.

I made reference to the Fred Hutch group in Seattle and their review of their experience in treating MS patients between the mid-1990s and 2006. They identified transplant-related mortality within 100 days of 2.8%, which obviously is more encouraging. But again, that's a highly specialized center; arguably, one of the best in the world at doing this kind of thing.

The good news is that as safety has continued to be focused on in the leading transplant centers, including here at Stanford, the complication and the mortality rate has substantially reduced. And under good skilled hands, we're looking at complication rates now that are less than 2%. But let's keep our eyes open to this.

We're talking about a therapy which ablates, or substantially compromises or suppresses the immune system. Our immune system is necessary for the prevention of infection and cancer. If it's suppressed, there's always the potential risk of a major complication that could be iatrogenic. So we have to be really assiduous and careful in using this kind of therapy going forward.

Adewuya: Moving on to phase 2 and some of the phase 2 results, could you assess any phase 2 results that compared stem cell therapy to standard of care, and showed clinically significant effectiveness? I would say that we've already alluded to some of it early in the conversation. But I also just wanted to call it out here.

Dunn: Yeah. After those initial results that showed a lot of promise that stem cell transplant type of therapy potentially could be helpful for people with MS, and we don't yet have a cure for, I think there were two major studies at the phase 2 level that were done that are worthy of our review.

One was called HALT-MS. This was led by Doctors Nash, Dr Mike Racke, Dr Jim Bowen. It began with the idea that we knew at that point that autologous hematopoietic stem cell transplantation was likely most beneficial for our patients with relapsing disease. And so the study looked at only patients with relapsing MS.

As with the others, a five-year survival was looked at in terms of how many patients enjoyed no recurrent MS relapses in a five-year period after treatment. And that number, I'm happy to say, was much higher. It was 69.2. So that was more encouraging.

It's important for us to realize that number was not 100%. I know some people are under the impression that this therapy potentially could be the cure for MS. But none of the numbers that we've seen have suggested that. It does look as if this therapy, when used for people with relapsing MS and chosen correctly, might have a substantial benefit in terms of decreasing relapses. There's no data that's out there that says we can knock that down to zero relapses at all.

Except that another phase 2 study led by Dr Mark Freedman and colleagues; he was in Ottawa. And a study in Canada specifically identified patients with aggressive-onset MS that were treated with a high-conditioning regimen with autologous hematopoietic stem cell therapy, transplant therapy. These patients enjoyed a 69.6% event-free survival over the study period.

It's rather remarkable. 24 patients were looked at who collectively had experienced 167 relapses going into the study. Then after treatment, really didn't appear to have relapses at all. And the MS activity-free survival rate at three years was documented, as I said, at 69.6%. That extended this idea that this therapy might be especially beneficial for patients with especially aggressive disease.

Now, those are the phase 2 studies, to answer your question. And now, as you know, a major phase 3 study that's likely to be considered the definitive trial in this field called BEAT-MS, is now underway, including at Stanford. We're actually active and enrolling for this study, even as we speak.

Adewuya: This is really exciting. I appreciate you level setting what those numbers mean for us. But I'm hearing you speak and I'm just like, "This is the step in the right direction." It sounds like we are getting closer to bedside use of these therapies, right?

Dunn: Potentially in the field of multiple sclerosis treatment, as you well know, we've enjoyed some really substantial progress. Where in the mid-'90s, there were no therapies that were shown in a statistically significant way to change the course of MS or to decrease relapse rate.

Since, the field has enjoyed this tremendous flowering of multiple therapies, now more than 20 different treatments, that if used in relapsing forms of MS, can show decreased relapse rate.

So we're in a situation now where it's not that we don't have any therapies. We have a lot of good therapies. Remember that the autologous hematopoietic stem cell therapy is associated with substantial risk. We're really talking about ablating the human immune system; and patients would be susceptible to infection during an epic time of their treatment.

The treatment we have already doesn't necessarily have that degree of potential risk or side effect to the patients. It may not have the potential benefit, either, because it may not be as strong. So there's a judgment call that we're going to have to make here, which is: is the extra risk of stem cell transplant therapy worth it for the potential extra benefit that it could offer? And actually, the BEAT-MS trial is designed to address just that issue.

Ruth Adewuya, MD (host):

Let's expound in that trial.

Dunn: Okay. In BEAT-MS, patients with MS who've had MS for less than 10 years, but have evidence of aggressive and very active disease, are going to be assessed. Then they're going to be randomized, with their consent, either to this autologous hematopoietic stem cell transplant therapy; and they would be aware that they're undergoing that treatment at the time; or best available therapy otherwise. There would be no patients that would be brought in who are going to be subjected to placebo, which would be unethical, obviously.

It addresses the question, even though we know that the stem cell treatment potentially could be effective, is it more effective than what we already have? Is it worth what we think is the extra incremental risk? Is it worth it to put patients through this, with the idea that their MS could improve ... but that they face a potential risk of maybe greater complications along the way as they're getting treated? Those are unanswered questions. And obviously, those are really key toward the clinical arena and clinical decision making.

Adewuya: What does BEAT mean? So it's B-E-A-T MS trial; is it an acronym?

Dunn: It is an acronym, and it speaks to the use of this transplant therapy compared to otherwise best available therapy. The title of the trial seeks to emphasize that this is not a placebo-controlled study. That patients that have aggressive MS are going to be treated with the best that we've got, either one way or the other.

And we're really leveraging the autologous hematopoietic stem cell treatment against aggressive immunotherapy that already has been FDA-approved to see if there are relative advantages or relative risks. Can we offer a step forward in our treatment of being able to help patients with MS or not? Is it a step backwards with respect to risk?

Adewuya: This is one phase 3 trial, the BEAT-MS study. are there other phase 3 trials to watch for in MS?

Dunn: I would say this is the definitive trial. This one is going to use the best sites in the country. It's going to have the greatest degree of recruitment. The numbers are going to be looked at perspectively and methodologically. I think the results of this trial will really help answer the question, is autologous hematopoietic stem cell transplant therapy worth it in MS patients?

I think the question is going to be, it's clearly not going to be for everybody. There are absolutely patients who have relapsing MS who have a mild form of the disease who need help, who need treatment, but don't necessarily need aggressive treatment and its attendant risks; who would benefit maybe from a more mild treatment with a lesser risk profile.

I think our charge here is to try to identify, is there a subset of men and women who have multiple sclerosis, who are especially well suited, or who seem to be especially likely to respond to a treatment like this? If we could identify that subtype and we could offer them superior therapy to what has been before, that represents a really important step forward in the field in general. And more importantly, for them individually and their families.

Adewuya: As we wrap up our conversation, I'm aware that clinicians who are listening to us, probably caring for MS patients that might be doing their own search in stem cell therapy and multiple sclerosis, and bring some of those questions to their clinicians.

What advice do you have for clinicians who are having those conversations with patients who are asking about stem cell therapy? What's the appropriate way to respond to those queries?

Dunn: I would validate that the stem cell therapy in general has great potential promise. I understand deeply what it is to be a clinician, and to look into the eyes of patients who are struggling and suffering, how much we want to extend ourselves and help them.

There are stem cell opportunities that their patients are likely talking to our colleagues about, who might be traveling out of the country to receive stem cell infusions, where the protocol may not be precisely defined. I would encourage patients here, as hard as that is to do sometimes ... The proper thing to do is to really study this and really get a good sense of benefits versus potential risks.

Some of the other subtypes of stem cell therapy that we've talked about, for example, with neuro stem cells and human embryonic stem cells, induced pluripotent stem cells: all of these have great potential theoretically, but some of them also potentially have risk, including tumor growth, as an example. Studies have not been done, in my opinion, that are sufficient to really allow us to define benefit versus risk with an adequate degree of clarity, to be suggesting this to patients who are in our care.

I think, though, mesenchymal stem cell therapy is relatively a little bit more advanced. Again, this is different than the transplant therapy, in that mesenchymal stem cells offer the potential of regeneration or restoration. There has been no trial that has shown clear benefit in a measurable, clinically significant way, as far as this goes yet.

But there are ongoing attempts, including early trials that are trying to look at mesenchymal stem cells, harvested either from marrow or even adipose tissue in some cases, to see if this can be used to restore damaged tissue in patients with MS.

That is hugely important. It needs to be looked at. But yeah, our colleagues that are listening should know there is no compelling or proven evidence of efficacy or therapy for that stem cell type. We need to continue to do research perspectively and rigorously to try to get at those answers.

Adewuya: Thank you so much for sharing your insights with us on this topic. What I heard from our conversation is the high potential and the incredible work that clinicians and researchers like yourself are doing to answer some of the questions that we have on stem cell therapy. And hopefully in the near future, we are able to see some FDA-approved stem cell therapy options for patients who, of course, desperately need it. Thank you again for taking the time to chat with me today.

Dunn: Oh, thank you, Ruth, so much for reaching out to increase awareness on this really important topic. It was a pleasure to be with you. And I hope that our listeners learned something valuable.

Adewuya: Thanks for tuning in. This episode was brought to you by Stanford CME. To claim CMEs for listening to this episode, click on the Claim CME link below, or visit medcast.stanford.edu. Check back for new episodes by subscribing to Stanford Medcast, wherever you listen to podcasts.

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Ruth Adewuya, MD, CHCP

Managing Director, CME

Stanford University School of Medicine

Course Director

Nothing to disclose

Jeffrey Edward Dunn, MD

Clinical Professor of Neurology

Stanford Healthcare

Faculty

Consulting Fee-Genentech, Inc. (Relationship has ended) | Consulting Fee-Alexion (Relationship has ended) | Honoraria-Bristol-Myers Squib Aventis (Relationship has ended) | Honoraria-Biogen Idec (Relationship has ended) | Consulting Fee-Janssen (Relationship has ended)

Ishita Verma

Student

Stanford University

Planner

Nothing to disclose