Episode 480: MSToronto 2026 with Dr. Jeffrey Cohen and Dr. Robert Fox

0:18 It's November 3rd, and we have a lot to talk about. Our coverage of MS Toronto 2026 continues this week, and in just a couple of minutes, you'll hear from two of the top MS experts in the world. Doctors Jeffrey Cohen and Robert Fox are both neurologists at the Cleveland Clinic, and they each led two very important sessions at MS Toronto 2026. But before we get to my conversations with Drs. Cohen and Fox, we have to talk about Christina Applegate. If you've been anywhere near social media, the news, or podcast feeds recently, then you heard all about Christina's stunning revelation that after years of publicly, courageously navigating what she was told was multiple sclerosis, her doctors recently informed her that she had been misdiagnosed.

1:08 Christina's raw honesty was heartbreaking to hear. She talked about feeling like she was back at square one, still dealing with very real, disabling physical symptoms, but suddenly stripped of the explanation and the medical roadmap she thought she had. Here, I'll just add that Christina did not let anyone down. The vulnerability she shared, the light she shone on invisible disability, and the comfort she brought to so many living with chronic neurological conditions, well, that remains invaluable. Misdiagnosis is a failure of diagnostic limits, not a personal failing. Now I want to address the elephant in the room, because over the past week, my inbox has been flooded with messages from our listeners, and the dominant emotion isn't just sympathy for Christina.

1:59 It's sheer panic. People are asking, if Christina Applegate had an entire team of top specialists and was wrong for five years, how do I know my diagnosis is real? Could I be taking the wrong medication? Could I be next? So let's take a breath, break down why this happened, and talk about what it actually means for you. Neurologists often call multiple sclerosis the great imitator, but the inverse is just as true. Dozens of conditions imitate MS. There is still no simple single blood draw or pregnancy-style test that lights up positive for MS.

2:41 An MS diagnosis relies on putting puzzle pieces together, including clinical history, neurological exams, spinal fluid analysis for oligoclonal bands, evoked potentials, and importantly, MRI imaging. The reason this picture gets cloudy is because nonspecific white matter lesions on brain MRIs can look very similar to MS plaques. Some of the conditions that frequently mimic MS symptoms and imaging include neuromyelitis optica spectrum disorder, systemic autoimmune and rheumatologic diseases like lupus, severe chronic migraines or microvascular disease, severe B12 deficiency, copper deficiency, or late-stage Lyme disease, and functional neurological disorder, or FND.

3:34 Studies from specialized MS centers, including Cedars-Sinai and UCLA, have shown that an estimated 15-20% of the patients referred to tertiary MS clinics with an initial diagnosis actually end up having one of these mimic conditions. It happens. Now, if you're currently questioning your own diagnosis, please hang on. Here are some things I'd like you to think about. First, your response to treatment tells a story. If you've been on a disease-modifying therapy and your routine MRIs show stable disease, no new active lesions and reduced relapse rates, your treatment is doing its job biologically.

4:19 That stability is functional proof of an active-responsive mechanism. Also, consider that diagnostic tools have radically advanced. The revised McDonald criteria, the wider adoption of spinal fluid analysis, and specialized imaging techniques, like looking for the central vein sign or cortical lesions, they make modern MS diagnoses far more rigorous and precise than they were even a few years ago. And specialist care can make a difference. Misdiagnoses most often occur when someone is diagnosed by a general practitioner or even a general neurologist who sees nonspecific white spots on an MRI and just stops looking further.

5:04 If your diagnosis was confirmed by an MS specialist or comprehensive neuroimmunology team using the full diagnostic criteria, the likelihood of an error, well, it drops significantly. If you're genuinely unsure of your MS diagnosis, rule number one is please don't alter your treatment regimen based on a headline. While your anxiety is understandable, do not stop your disease-modifying therapy. Abruptly discontinuing certain MS treatments can trigger severe disease rebound. This is especially true if you're on Gilenya, Mazent, Zeposia, Ponvary, Tysabri, and Tyruko.

5:47 And at your next routine visit, ask your neurologist to walk you through the specific criteria that solidified your diagnosis. A good clinician will be happy to review your Spinal Tap results, the specific location and architecture of your lesions, and your clinical timeline with you. If you're someone who was diagnosed years ago after a single MRI scan, you've never seen an MS specialist, or you have symptoms and atypical MRI features that have persistently surprised or confused your care team, getting a second opinion at an accredited MS center is always a reasonable, proactive step for you to take.

6:29 Christina's journey is a sobering reminder of how nuanced an MS diagnosis can be. But please know that her story does not invalidate your reality, your care plan, or the stability and quality of life you work hard to maintain every day. Few sessions generated more buzz at ms toronto 2026 than the discussions surrounding car t cell therapy. Dr. Jeffrey Cohen of the Cleveland Clinic co-chaired one of the standout presentations exploring its potential in treating multiple sclerosis and we sat down with dr cohen directly following the session for an update on the latest clinical findings Dr. Jeffrey Cohen is a neurologist at the Cleveland Clinic's Mellon Center for Multiple Sclerosis Treatment and Research, where he also serves as a director of the Experimental Therapeutics Program.

7:29 And one of the things Dr. Cohen is doing at MS Toronto 2026 is moderating a session focused on CAR T-cell therapy and immune system reset in MS. It's good to see you, Dr. Cohen. It's good to see you. I hope you'll start us off by briefly explaining what CAR-T cell therapy is and what's meant by an immune reset. Yeah, so CAR-T therapy is an area where there's a great deal of interest. It's early days, but so far the results have been very encouraging. So what a CAR-T cell is, a so-called effector T lymphocyte that's been engineered to express a CAR or chimeric antigen receptor.

8:10 So this is an artificial receptor that's able to target specific antigens or other molecular targets on other cells. And then what it allows for is for antigen recognition that doesn't require MHC, which is one of the requirements of typical antigen recognition by the immune system. Then activation of that CAR-T cell, proliferation, and ultimately killing of the target cell. So that approach has really revolutionized the treatment of hematologic malignancies, lymphoma, leukemia, multiple myeloma.

8:55 And the CAR-T cell products that are already approved to treat those malignancies target antigens that are expressed on B lymphocytes. And so So the thought was, is that because we know that B lymphocytes play such an important role in the MS process, that maybe we could utilize this approach to treat MS. So, among our most potent MS therapies are monoclonal antibodies that target B cells. The advantage of CAR-T therapy that does somewhat the same thing is that whereas monoclonal antibodies only target and kill B cells circulating in the blood, CAR T cells have the ability to migrate throughout the body and kill those B cells in the tissues, including within the central nervous system, which antibodies can't penetrate.

9:53 So you asked about immune reset. So the idea is that CAR T cells may have very potent benefit by killing B cells, deeply depleting them in the blood and in the tissues. And then, as they reconstitute, repopulate, that the B cell population may come back with a more normal characteristics, a more normal regulatory phenotype, and a more naive phenotype characteristics, the idea being that the immune system may be in a more normal state after reconstitution. So that's the reset.

10:37 So the hope, the goal is, is that CAR-T therapy may be a very potent treatment, and it also may be a very durable treatment. You know, as you mentioned, CAR-T therapy is already used to treat some cancers. Early oncology treatment, CAR-T cell therapy targeted a disease that was highly resistant to other forms of treatment. In multiple sclerosis trials today, we see cohorts spanning both treatment-resistant relapsing disease and non-active progressive MS. Where do you believe CAR-T cell therapy has the highest likelihood of providing transformative clinical benefit, and who represents the ideal candidate?

11:20 Right. As I said earlier, it's still very early days with CAR T. So far, the published data really only includes several small case series. There are a number of more formal phase one studies that are ongoing, actually quite a large number of those. And several of those are going to be reported out. Some preliminary ongoing data from those studies is going to be reported out at this meeting. I think it's very likely that CAR-T therapy directed against B cells will be effective in treatment refractory relapsing MS, because it's pretty likely that the CAR-T will accomplish at least the same thing that the B cell monoclonal antibodies do.

12:12 But that's a population for whom we already have a sizable number of treatments. Now, there are a few people that don't benefit from that, from those therapies, still have ongoing disease activity, but I think that's going to be a relatively small population. I think the population that I'm most excited about is people with non-active, non-relapsing, progressive MS. Our current therapies don't target that effectively almost at all for most people. And so the hope is that CAR T cells, through their ability to get into the nervous system and address the mechanisms that drive progression within the nervous system, that they'll be effective in that population.

13:02 And so far, very early results look very promising in that regard. In hematologic oncology, CAR-T therapy carries some significant risk of side effects like severe cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome. What are early safety and tolerability signals revealing among people with MS? And how are conditioning protocols being modified to minimize toxicity for neurological patients? Yeah, so there's several questions in there. So, one is there's actually quite a lot of experience with CAR-T to treat hematologic malignancy. So, the range of potential complications is pretty well defined.

13:47 And so, as neurologists, we, in fact, see some of those patients because some of those toxicities are neurologic, even though they're cancer patients. Some of the same toxicities have been seen in autoimmune diseases, including multiple sclerosis. However, actually, thankfully, it looks like they're less frequent and less severe, in part because the target cell burden is lower. Cancer patients have a huge number of the target cells that the CAR-Ts see and get activated by and kill, whereas the number of immune cells that are killed in a patient with autoimmune disease is much smaller.

14:29 So, there isn't quite as frenetic a response by the CAR T cells. And as a result, some of these well-known toxicities seem to be less common. Now, we were concerned that someone that already has an immune condition, where their immune system may be overactive, or that already has a neurologic disease, might be more prone to those complications. But thankfully, that so far has not been the case. You asked about a couple of other things. Currently, low-dose chemotherapy prior to the CAR-T is a standard part of the regimen. That's mostly to make room, as it were, in the immune system for these CAR-T cells.

15:13 There are some considerations about whether that's really necessary in an autoimmune disease. You don't need quite as robust a CAR-T response, or whether at least the regimen could be toned down a little bit. And then there's also a development called in vivo CAR-T. So the current approach to CAR-T is you produce them in the laboratory, then re-infuse them into the patient. But there is a technology for creating them within the patient, and that may not require this lymphodepleting chemotherapy. So that's really exciting. The field's moving really quickly, so we'll see how that goes.

15:56 That is really exciting. We have to bring up two pharmaceutical manufacturers not too long ago paused their CAR-T clinical trials after three trial participants passed away. What's the readout from those deaths, and how have those paused trials impacted the work going on in this area? Yeah, so it's… You know, first of all, you know, the tolerance for risk is lower in autoimmune diseases. You know, in patients with hematologic malignancies who may die because of their disease in the near future, you know, the oncologists and the people with cancer are sometimes willing to put up with bigger risks.

16:36 We're not going to tolerate that in treating MS and autoimmune diseases. So, those two instances that you mentioned did give us pause. They did remind us that CAR-T therapy is a very novel experimental therapy. I don't know all the details from one of those, but I think in both cases, probably the main cause related to the manufacturing protocol. What we're finding is that the shorter manufacturing procedures lead to CAR T cells that are more active, and the dose of the CAR T may need to be decreased with these newer manufacturing protocols.

17:22 You have extensive experience as an expert in autologous hematopoietic stem cell transplantation. Both approaches aim for an immune reset, but through very different biological routes. How do you compare the curative or long-term remission potential, durability, and practical delivery of an engineered living CAR T-cell product versus high-dose chemotherapy followed by stem cell transplantation? Yeah, so the situation is really different for those two treatment approaches. For hematopoietic stem cell transplant, we actually now have a sizable amount of experience. We know the good points and the bad points. It's a very effective approach in appropriate candidates, but it's a pretty rough procedure.

18:09 So, whereas CAR-T is a promising approach with very encouraging early experience, but very limited experience so far. So, on the good side, it's a much less rough approach. So, I would say that if CAR-T pans out, it may obviate the need for a metapoietic stem cell transplant in many people. But unfortunately, our experience in the field has been that some things that seemed like a good idea didn't work out as well as we had hoped. I guess that's what science is all about. Well, Dr. Cohen, I want to thank you for all you do to improve the lives of people who are living with MS.

18:55 I can honestly say I learn something new every time we talk. And thanks so much for making time to talk with us today. It was great talking to you. Progressive MS was front and center at MS Toronto 2026, where Cleveland Clinic's Dr. Robert Fox led a packed session highlighting the global collaborative work of the International Progressive MS Alliance. Prior to this session, Dr. Fox talked with us about the impressive portfolio of work being driven by the Alliance. I'm here with Dr. Robert Fox, and I have to say, it's difficult for me to attend a major MS research conference anywhere in the world and not want to talk with Dr. Fox.

19:39 He's a neurologist at the Cleveland Clinic's Mellon Center for Multiple Sclerosis Treatment and Research, as well as a vice chair of research at the Cleveland Clinic Neurological Institute. But Dr. Fox also serves as a principal investigator for some of the most high-profile clinical trials for multiple sclerosis. He chairs the International Progressive MS Alliance Scientific Steering Committee, and Dr. Fox is the Managing Director of the NARCOMS Patient Registry. So when you consider his leadership role in so many aspects of multiple sclerosis research and care, there's always a good reason to catch up with Dr. Fox. Thanks for joining me in Toronto. Well, thanks, Jon. It's always good to be with you. One of the things you'll be doing at this meeting is delivering sort of an update on the International Progressive MS Alliance.

20:25 When the Alliance first set out its agenda, treating progressive MS was, was widely considered one of neurology's hardest challenges. And the strength of the Alliance came from its global collaborative model, which was a novel concept when the Alliance was launched. So as you present this update here at MS Toronto 2026, where, or how do you see this global collaborative model has moved the research needle the fastest? So this global collaboration truly has brought together academics, nonprofits, industry, people affected by MS like yourself. You were a part of the Scientific Steering Committee for many years.

21:08 Thank you for your contributions to that. Pulled together to try to solve the riddle of progressive MS. And there were three main areas that were identified and continue to be our central core focus to solve the riddle of progressive MS. One is what is the true biology? What are the pathogenic mechanisms that are driving progressive MS? There are many different things that are thought to be a part of it. It's probably not all of them. What is the real pathology? We're still trying to figure that out. Secondly, how do we accelerate The discovery of new therapies? How do we make clinical trials faster and more efficient so we can identify the promising therapies and carry them forward and reject the therapies that don't have any promise moving forward?

22:01 We don't have a good way of separating the wheat and the chaff, if you will, and we need to figure that out better. And thirdly, people affected by MS have a lot of symptoms, a lot of issues with their just everyday function, whether it be fatigue, bladder dysfunction. Walking difficulties, spasticity, all these symptom problems that we might be able to address the disease mechanisms. But if we don't help them function in their everyday life, we will not really have helped them in a way that they want to be helped. So we continue to focus in those three areas. We have funded research in each of those areas to try to identify solutions and overcome some of the barriers.

22:49 We have convened groups to pull together to try to brainstorm and identify better solutions. We've even met with the regulators. We had a meeting with the U.S. FDA to talk about fluid biomarkers and to develop further progress in understanding fluid biomarkers that may reflect progressive MS. So there are many different areas that we have been involved, and we're just getting started. The Alliance's scientific mandate focuses heavily on accelerating drug discovery, identifying novel targets, refining clinical trials. What are the top priorities the Scientific Steering Committee is driving right now?

23:33 So at the beginning of this year, the beginning of 2026, we took a step back and we said, OK, we've been doing a lot of things over a lot of years. Let's take a step back and see where we really need to go. We stayed with our three focuses, the biology of progressive MS, accelerating trials and improving the quality of life of people living with MS. And we convened task groups that did a deep dive to identify what are the remaining unmet needs? What are the remaining problems and what should be done? What are the critical things that need to be done now to help us make progress?

24:15 And so over the course of the last nine months, we brainstorm, we put together those ideas, we refine them in person this past summer in a convening effort, And we continue to do that now. And we have identified some of the critical barriers in understanding the biology and accelerating the trials and improving quality of life that we will then implement over the next three to five years. So taking a step back and saying what really needs to be figured out and then identifying the steps to go figure it out. Well, speaking of accelerating clinical trials, in an effort to accelerate research, we're seeing multi-armed trials like Octopus and the Platypus trial that test multiple drug candidates simultaneously.

25:03 How is the Alliance collaborating with academic groups and industry sponsors to make trial screening faster, cheaper, and less burdensome on the trial participants? Well, we are supporting these multi-armed trials. One, we also identified through this strategic reflection that the alternative trial structures of different ways of doing trials, like the multiple arm adaptive trial design, like the octopus and the platypus trials, they are important aspects of what we need to get out into the world for people to know them. There are some other designs of doing trials, such as futility design trial, which is a little bit different than a superiority, a benefit trial.

25:54 And so what we've come to realize is we need to promote them. We need to let the field know about them more, particularly the sponsors, like industry sponsors and government sponsors, So they realize that those are useful and valid trial formats that can test new therapies faster and more efficiently. Stopping progression is critical. At the same time, as you started to point out, day-to-day life for someone with MS is dictated by symptoms like fatigue, mobility loss, cognitive fog. What updates can you share regarding the Alliance's work in non-pharmacological interventions and neurorehabilitation? .

26:34 Well, we are actively supporting several trials that are exploring non-drug approaches to improve quality of life of people living with MS. And so we are directly supporting those trials and helping to identify those potential treatment methods that don't involve drugs. In addition, through the strategic planning, we have identified a need to establish a new conceptual model of quality of life and what that means to people living with MS. And so over the coming year, we will be trying to develop that and establish that, a new conceptual model of living with MS and progressive MS particularly.

27:22 The Alliance has made, including people affected by MS, a cornerstone of its work. As you were kind enough to point out, it was my privilege to serve as a member of the Alliance Scientific Steering Committee. So I know how I would answer this question. I'm curious from your perspective, how have you seen the direct involvement of people affected by MS impact the Scientific Steering Committee's clinical or research priorities over the years? We value deeply the ongoing continued input of people living with MS. That's why we have three people affected by MS on our scientific steering committee. And we have even more that are on an engagement committee.

28:04 Because if we don't listen to, pay attention to, and get input from people living with MS and affected by MS, we are not going to be on the right course. And so we are continually getting input. As late as our Scientific Steering Committee yesterday, we had many, inputs from the Scientific Steering Committee members who are living with MS to help guide us, to focus us, to refine us. It keeps us on target and makes sure we know that we're going in the right direction. While we're talking, I'm wondering if we can switch gears for a minute and talk about something called the MONARCH trial and the Primrose clinical trial, both focused on an experimental medication called orelabrutinib.

28:52 Orelabrutinib. Yeah, it's a tongue twist. The MONARCH trial will test the drug among people with secondary progressive MS. Primrose trial will test the same drug among people with primary progressive MS. Orelabrutinib falls under a category of disease-modifying therapies called Bruton's tyrosine kinase, or BTK, inhibitors. And BTK inhibitors have gained significant attention for their dual mechanism, modulating B cells in the peripheral nervous system, but also crossing the blood-brain barrier to attacks targets like microglia in the central nervous system. How does olabrutinib compare with earlier BTK inhibitors?

29:32 Well, in the past, before BTK inhibitors, we have found the effect of one drug in a class to be very similar to other drugs in the same class. Whether it's an S1P modulator like fungolamide or an interferon or a B cell depleting therapy, within the same class, they all work kind of similarly. What we are finding with BTK inhibitors is that if you understand how one BTK inhibitor works, you only understand how one BTK inhibitor works. They work very differently from one drug to another. And we haven't yet figured out how to predict how one drug will work.

30:16 In terms of their effect on B cells or microglia, also their effect on the relapsing pathology, which we think is mediated by the immune system out in the periphery, out in the circulating blood and the lymph nodes, versus the compartmentalized inflammation, meaning the inflammation within the brain. And what we found is different BTK inhibitors work differently on that relapsing pathology and the progressive pathology. What has me excited about oral abrutinib is that it appears to have a strong effect on the relapsing pathology. That effect continues for a long period of time, which was a problem that we had with some of the previous BTK inhibitors like evobrutinib and that its effect on relapsing pathology was brief and short-lived.

31:04 With orelabrutinib, it seems to continue long-term, and it crosses the blood-brain barrier in a biologically relevant concentration. So we think it will have an impact within the central nervous system on that compartmentalized inflammation that we think drives progression. So we have a bunch of reasons to believe that it should work in progressive MS. And I'm happy to see that the sponsor is doing a trial in secondary progressive MS and primary progressive so we can learn in those two different forms of MS, which are probably more similar than they are different, but nonetheless, they are still considered different forms of MS and we'll understand the effect from those two trials.

31:49 I'm trying to recall, am I right, that orelabrutinib is an oral medication? Yes. So, you know, that's interesting in itself Because people who are living with progressive forms of MS have largely been left out of the oral medication options for a lot of time. How do you think the possibility of having a once-daily oral medication is going to impact things like adherence? Well, at one level, I think people living with progressive MS aren't going to be too picky about how they get their effective therapy, whether it is an injection, an infusion, or an oral pill. But, of course, a once-a-day oral pill is going to be much more convenient and easier for patients to take.

32:34 So I think it's going to be much more embraced and preferred by people with MS. Are these two clinical trials for this new medication currently recruiting participants? They are. They are recruiting both in primary progressive and in secondary progressive MS, and recruitment is all around the world. So those who might be interested in participating can look around a Google search, a clinicaltrials.gov. There are many websites that can help direct them to a site, hopefully close to them, where they can explore whether they could participate. You know, we'll try to make that easier. We'll include some of those links in the show notes for our episode.

33:16 I would say the other thing that's exciting about BTK inhibitors, and we don't know if oralibrutinib falls under this category, but it very well may, is that some of the BTK inhibitors suppress B-cell function. And so they may work on the relapsing pathology in part similar to what the B-cell depleting therapies do, but without depleting the B-cells. So it's pointed us towards some of the potential mechanisms that the B2K inhibitors may work on relapsing pathology while still allowing them to go into the brain and downregulate some of the compartmentalized inflammation within the brain. Dr. Robert Fox, I want to thank you for all that you do in all of the many roles that you managed to excel at filling. Thanks so much for talking with me today.

34:06 Well, thank you, John, and thank you for translating the very complex field of MS into something that's very understandable. So thank you for that. That's going to wrap up this episode of Real Talk MS. Real Talk MS is powered by the National MS Society, and you can share this episode of the podcast by letting your friends or family members know that all they have to do is point their web browser at realtalkms.com slash 480. You'll find that link in today's show notes, so you can easily copy and paste it right into an email or a text. I also want to invite you to download the free Real Talk MS app for your iOS or Android smartphone or tablet.

34:47 It's the best way for us to stay connected. The app will automatically download the latest episode of Real Talk MS. You'll be able to download and listen to past episodes. You'll be able to save your favorite episodes. And what I'm particularly excited about is that I'll be able to share all kinds of bonus content with you. And that content will only be available on the app. So I hope you'll take a minute to visit the Apple App Store or the Google Play Store and download the free Real Talk MS app. And you'll find those links in today's show notes or at realtalkms.com. Next week, we're wrapping up our coverage of MS Toronto 2026 with a deep dive into a subject that seemed to be everywhere at this meeting.

35:34 It was even embedded in the theme of the meeting itself, and that subject is unifying MS. We're going to look at what that really means, and most importantly, how this kind of a change will impact your MS care. This is a subject that's going to affect every person living with MS, and that makes this an episode you won't want to miss. I'm Jon Strum. Thanks for listening. Stay safe and make healthy choices.