Hope in Innovation: Exploring CAR-T Cell Therapy for MS

Hope in Innovation: Exploring CAR-T Cell Therapy for MS

Episode 178 – Podcast Transcript

[music] [(0:25)] Stephanie Buxhoeveden: Welcome to the Can Do MS Podcast. I’m your host Stephanie Buxhoeveden. I live with MS. I’m also a clinician and MS researcher. Today I look forward to welcoming our guest, Dr. Gregory Wu, who’s a neurologist and scientist from Washington University in St. Louis. He’s doing incredible work in MS research, including CAR T-cell therapy, and I can’t wait to dive into our conversation and learn more about his experiences and insights. Hi Greg. Welcome to the podcast.

[(0:51)] Gregory Wu: Well, thank you so much for asking me to join you. It’s a pleasure to be here.

[(0:54)] Stephanie: Awesome. Well, to start, I’d love to just hear your story. What first inspired you to get involved in the field of MS and how have you seen it change over the course of your career?

[(1:04)] Gregory: I’ve been interested in multiple sclerosis for quite some time, based primarily on my interest in research and how the nervous system and immune systems interact. My PhD is in neuroscience and my experience, my first experiences in research were through more traditional neurodegeneration, cellular neuroscience fields, but it became clear to me as a young student that the immune system is really important in the nervous system as well, and those two systems interact quite significantly. So a little niche sort of area of interest I think blossomed into trying to understand diseases that inter- that form from the interaction of both of those systems, and so multiple sclerosis I think is one of the quintessential diseases that we think of in neuroimmunology.

I also became really interested in multiple sclerosis based on friends whose family members have been involved, and unfortunately some of my family members were diagnosed with multiple sclerosis. So it’s kept me very, I think, passionate about what I do. The changes I’ve seen since early on really encompass so many different things, both in terms of identifying what multiple sclerosis really is, identifying diseases that are very similar to multiple sclerosis and now splintered away from that, and then therapies. I think that the real change, the game changer in our field has been the emergence of what we refer to as disease modifying therapies. When I was in medical school, the very first disease modifying therapy was approved for multiple sclerosis and it’s been just an avalanche of discoveries and approvals and employment of these therapies that have kept me really, I think, excited about this field and this clinical disease.

[(3:05)] Stephanie: Yes, I agree. I find it really exciting. I know in the time between when I was even diagnosed and now there’s so many more treatment options that we can offer people, and I think that’s really, really exciting, and as you mentioned, we’ve come a long way and in terms of medicine in a relatively short period of time over the last few decades. So looking ahead, what do you think the future of MS care and research looks like and what are you most optimistic about?

[(3:34)] Gregory: I think there are a lot of different areas that still are quite rife for opportunity in major advances- major- in major advances for multiple sclerosis. I think one of the things that I’m most excited about that we’ve been really sort of a buzz with is the continued refinement of understanding what the definition of multiple sclerosis is. So that in the short term, I think will play out and be very meaningful in capturing the right people who we apply these therapies to, understanding what causes MS because we have a better handle on what is MS. And that of course will be, I think, a thread that we continue to develop, not just in the short term but long term. Similarly short term, I think that some of the emerging disease modifying therapies are really going to be a big influence on how we continue to I think innovate in- in treatment of multiple sclerosis and changing the way in which we are able to intervene very quickly in patients’ lives.

I’m referring to the recent identification that bruton’s tyrosine kinase inhibitors, for example, seem to be effective in slowing the progression of disability in multiple sclerosis, and then even newer avenues of therapy CAR T cells I think are going to be really impressive and hopefully will be a unique avenue for which we can explore treatment options for different patients. I wanna also just include the fact that even longer term, I am optimistic that there will be therapies that will be able to use that will be- that will be really I think, important to repair the nervous system to- to encourage remyelination, for example, or be protective to neurons and nerves in the setting of inflammation within the brain and spinal cord. But I think those are very long-term aspirations, which have been around for quite some time. We’re closer to being able to identify different therapies in that arena. But perhaps we can focus on CAR T cells as really, I think a emblematic therapy that’s being- that’s being developed currently that might be a little bit more available soon.

[(6:00)] Stephanie: Yes, and you said a few very important things, right? Because I know this matters a lot to me and to the patients I used to treat, you know, it seems like a basic question, why did I get MS what caused it? And we still don’t truly know. So that information is so valuable because once you understand the root cause of something, then you can really start, as you said, personalizing the treatment, hitting it at the source. And you mentioned a couple of new types of medications that are coming. CAR T specifically is gonna look different than any other treatment we really currently have for MS, and most of us probably are- have never heard of it or are definitely not familiar with it. So could you please explain what CAR T cell therapy is and how it’s being applied in the treatment of MS?

[(6:48)] Gregory: Sure. So CAR is an acronym C-A-R that stands for chimeric antigen receptor, and I’ll explain that in just a second. Then the T cell part of that is the type of lymphocyte that we all have in our body. The type of T cell matters here, but the general premises that we’re taking an immune cell and sort of harnessing what the immune cell would typically do that is kill or modify or target a particular element that’s in the body and a T cell comes in two different flavors. But the way in which I think most of the current, or at least the most, how do I say that? They’re, you know, the- the newest iterations or the- the sort of first wave of these therapies coming would be based on a type of T cell called a CD8 T cell, and these T cells are known or can be used to kill. The body uses CD8 T cells to kill a target and that target typically would be a viral infected cell in our body or a cancerous cell. And I think the revolution in immunology came in several waves. The first was the recognition that our immune system is actually harnessed in this manner. That is to say the T cell can be a really critical element in our immunity to fight off infections and cancers and how it does that through these CD8 T cells is still being researched and really heavily investigated. But the premise here is that if we could take a T cell that’s designed to kill like that designed to target a bad element in our body and then tell it what to recognize specifically, then that would be really helpful.

And so in this instance, the chimeric nature of the T cell that’s being engineered for a therapy is done so by modifying two different parts in the T-cell, the outside part, the recognition part, the receptor part, so that R in CAR the receptor is something that we have been able to modify or engineer so that we can target the killing to something very, very specific. In the newest sort of case, I’d say we are looking at something very rudimentary, which is to target a B cell surface protein CD 19 for example, that is a molecule that most B cells express. So then the CAR T cell using the receptor that sees only CD 19 will kill only CD 19 positive cells. That is B cells. The internal part of that CAR construct that is the molecule that represents the CAR, the chimeric antigen receptor is a signaling device that controls whether when the receptor is engaged, the T cell becomes activated and kills and it sort of enlists that function from the T cell to say, yes, this is in fact your target now destroy it. So the engineering part of this really is how do we glom on the outer portion to the inner portion and really create a very efficient and selective immune cell that will kill what we want it to.

[(10:27)] Stephanie: Yeah, I think that’s fascinating and it’s very clear, you know a lot about neuroimmunology [laugh]. So in other words, basically we’re taking an immune system that is incorrectly fighting its own body and you’re using that T-cell that’s already there inside the patient and you’re teaching it how to specifically kill the cell that’s misbehaving. Did I get that right?

[(10:54)] Gregory: I like that analogy and I think that sometimes we also use a military analogy or an army. So maybe one way to look at this is in multiple sclerosis, part of the army has gone rogue and we don’t want those bad actors to continue to cause injury to the nervous system and so we are actually training the soldiers in our military that would normally look outward and- and instructing them to go look for the bad actors inside the army, you know, that it comes from, and in this instance we’re using a selective device to say, “We’ll give our army, the good army members, the CD8 T cell, a sort of scope that only sees the bad guys and then give them a weapon that will shoot when their, you know, scope or their- their ability to see those rogue bad traitors in the army to kill them and only them.”

So now you’ve trained this T cell or this army member, the selective army member in a way to get rid of and call out the bad actors here that are really responsible for disease. Yeah. It’s kind of ironic, like you said, you know, we think of our immune system as sort of one entity, but like you said, there are bad parts that we have been able to sort of identify in MS that we wanna get rid of. The question is how we do that. Currently, a very effective disease modifying therapy involves depletion of B cells already, and that’s a monoclonal antibody strategy. Multiple products do that. The innovation here is that we’re using a living drug, a T cell that’s part of our immune system that’s already sort of, you know, used to do good things and turning it around to try to eliminate these B cells that- that should have good benefit the way we’ve seen with B cell depletion therapy.

And I’d like to just extend that by saying we don’t wanna make a carbon copy of what already exists. So one of the ideas about using CAR T cells is the fact that it might have the advantage to go places where our current therapies can’t reach in the body. For example, these B cells, the bad guys that we think could be responsible for driving MS disease might hide out inside the skull and spine in this layering called the meninges, where monoclonal antibodies that are used now to target them for depletion can’t reach. And a CAR T cell, because it has the same properties of the rest of our immune system, can move around the body and go to places like the meninges, like the brain and spinal cord territories that a monoclonal antibody can’t reach and then get rid of those guys who may be, in fact the most deleterious, the most injurious of the B cells that are in our body during MS.

[(14:07)] Stephanie: Yeah, and essentially you’re making the immune system behave as it should, right? Because normally our immune system would recognize a cell that’s misbehaving, it could potentially target the body or what we call autoimmunity and kill it. So you’re- you’re teach- you’re reteaching it how to behave well, and all of our current therapies, they either modulate the immune system, change the way immune cells behave, or like you said, if all else fails we just kill the cell, right? But that involves a medication that you have to give yourself either once a month or sit for an infusion every six months and so you’re relying on that medication to deplete and you have these sort of like peaks and plateaus of- of B cells, whereas this would be a continuous, as you said, soldier that patrols around the body and sort of restores that function, which I think is really great and it sounds like it has the potential to be a game changer in MS. So do you think therapies like this would open new doors for helping to personalize medicine and get more targeted treatments?

[(15:10)] Gregory: Yeah, I’m- I’m very hopeful for that. But as a real senior colleague in our field has told me like, the experiment needs to be done, we don’t know. And I think it’s really important that we do understand whether CAR T cell therapies can be used for MS for several reasons. One, MS has been a vanguard in many respects for other neurologic conditions. So if we answer this question for MS, it may be immediately applicable to other neurologic diseases and that’s one thing that we have to sort of shoulder the responsibility for. Number two, I think it’s important to realize what you touched on earlier is that we do a lot of this sort of understanding of the pathogenesis or the cause of MS through reverse engineering if this medicine succeeds or even if it doesn’t, we’ve learned something more about the disease and how it actually goes about driving disability and- and developing, you know, sort of features of autoimmunity that we don’t understand currently. So in a way, testing the CAR T cell therapy and- and one aspect such as tissue localization of these immune cells and the CAR cells could be really instrumental in understanding more about MS fundamentally. And then the third thing is exactly like you said, personalization.

CAR T cells are actually much, much more than a cellular targeting killing device. Others have really, I think, espoused the idea that their delivery vehicles as well, and if we want- really wanted to get clever and- and really cute about it, which many scientists have already in animal systems for example, we could combine a whole payload of good things to the nervous system along with targeting some factor that could be bad, giving a growth factor, providing myelin encouraging features as well as killing bad immune cells or without even killing, we could tell this CAR T cell to do something that’s really helpful for the microenvironment where it ends up. That could be again, growth factors or proliferation for myelin producing cells, any number of things. If we could engineer the CAR T cell to have some sort of homing and recognition and do something special, that would be very personalizable.

And then the last thing I’ll say about personalized CAR T cells is something that we are pursuing in our laboratory in collaboration with really ingenious scientists to try to understand not just what immune cell as a category are bad, but those immune cells have receptors too, they’re very specific. So rather than getting rid of all B cells, let’s just get rid of the B cells that are being too aggressive and specifically targeting myelin for example, or let’s get rid of the T cells that talk to the T cells to do that and those T cells also have very, very selective specificity. So instead of wholesale getting rid of a category of immune cells, let’s do a surgical approach. And in individual patients those surgical targets may be different. One person’s MS is certainly different than the next person’s, and perhaps that difference is based on immune cell specificities so that we could say for one person, this is the CAR T cell we need to use and the next one we could engineer it to be slightly different because that’s what that patient needs.

[(19:03)] Stephanie: Yeah, I think that’s very exciting, and like you said, everyone with MS is so different, so it seems only logical that each person will need a slightly different treatment and that is coming closer and closer to being a realistic goal. As we alluded to before, this therapy will be very different than something you inject once a month or sit in an infusion chair twice a year for, can you tell me a little bit about what the CAR T therapy process looks like? And of course people who know cancer might already know, but this is a new concept to MS.

[(19:42)] Gregory: Yeah, it’s early days, so I don’t want to sound as if there’s a definitive answer to that. I’ll tell you that in broad strokes, there are a few ways in which we envision this being used. In general though I agree Stephanie, that what we’re trying to do is to give a durable treatment that won’t be one of these you know, continual visits or infusions or things like that. But there are, you know, large differences in the way in which we could approach this. And again, like you said, this is already being innovated in the cancer world because CAR T cells can be used to target cancerous cells like we just mentioned, and we would say, “Oh, this cancer expresses a very selective target, let’s use that as the receptor for the CAR and go after that and kill it,” and that works.

So the way in which I would say in our field of MS, we’re- we’re sort of anticipating this being used is one of a few ways. The first would be what we refer to as autologous, patient comes in, we gather their T cell, we produce a CAR T cell with their own T cell by modifying it with the construct that says, now your T-cell is going to see this target, let’s just say B-cell expressing proteins like CD19. We also in that CAR say that when you see that target kill it, and so when we take the immune cells from that patient, they’re their own, we’ve engineered them, we put them back into them and expect that that will be very effective in reproducing a beneficial clinical response. There’s a- a sort of need to have a facility locally typically that will be able to do that and do it quickly enough so that by the time we’ve taken the cells out and we put them back in, there hasn’t been too much of a lapse in time.

Alternatively, a different strategy that’s already being sort of employed and proposed for these trials that are ongoing is to take what they refer to what- what others have referred to as off the shelf products. Taking a- a generic immune cell from a donor that’s unrelated to the patient making the same modifications, but that would fit any number of different recipients with MS. Off the shelf CAR T cells have the advantage of really being deliverable almost immediately. Someone comes in, we say, “You’re a candidate for this, let’s grab one of these, we’ll infuse it in you and then we’ll be done.” In both instances by the way, at the moment what’s envisioned is that the CAR T cell needs to be delivered in the setting of an immune suppressive drug for several reasons. But the main one that I’m aware of is the fact that there’s no space for these cells in your body. It turns out all of our immune cells are kept at specific ratios to other cells, you know, based on fairly complicated cues. And so to- to kind of sort of give an analogy, if you’re invited to a party that’s already full, you’re gonna be waiting outside for a while or you might leave.

And so in our bloodstream, you know, if we try to give these CAR T cells and there are too many people in the party, too many T cells already there, the CAR T cells might not be able to survive and do their job. So one reason to give these powerful immune suppressive drugs is to kind of eliminate wholesale, empty the rooms of the party just ever so slightly so that there is an availability for these CAR T cells to set up shop. And I think that’s a really interesting but problematic aspect of the trials at least, that is to say those drugs in and of themselves can have effects on autoimmunity, can be toxic, and might- might not actually agree with some patients. So we’re being a little bit, I think, cavalier in- in sort of expecting, I should say to answer your question, how these drugs will be employed because it’s really early days, like I said.

[(23:35)] Stephanie: Yes. Yeah, very early days and very exciting. And of course early days of research, you know, this is just now starting to be brought to MS patients for study. Which begs the question, how do people who are interested in participating in this revolutionary research, whether it’s CAR T cell therapies or other clinical trials, how do they get involved or just learn about what’s going on?

[(24:03)] Gregory: I’m fortunate to be at an academic center where we really highlight the availability of ongoing trials. I realize that that’s not the case for patients across the board and certainly for your listeners, I’m not sure how many have access to an academic center, but I would start with talking with your provider, asking them if they are aware of opportunities to be treated with CAR T cells experimentally at the moment in clinical trials. I like to recommend the National Multiple Sclerosis Society as one portal to understand what trials are going on. There are web pages for all sorts of approved and experimental disease modifying therapies on the nms.org website. I also encourage folks to look at clinicaltrials.gov where you can search for any number of diseases and any number of different trials even just so far as to kind of, I think peruse what the clinicaltrials.gov says is available for CAR T-cell therapy and autoimmunity may be instrumental. But the bottom line is talk to your doctor, talk to your clinical provider, ask them if they’re aware of any of these trials, ask what their opinion is of these new therapies and whether or not they may be a good candidate for a trial like that.

[(25:25)] Stephanie: Great. Thank you so much for sharing your knowledge and your insights with us. You’ve had a fascinating career and I know I’ll be following your research very closely.

[(25:34)] Gregory: Thank you so much for asking me to have this discussion with you. I’m very hopeful for these therapies and other innovations for multiple sclerosis, so I know this type of conversation is not over.

[(25:45)] Stephanie: Awesome. Thank you. Thank you for listening to this episode of the Can Do MS Podcast. If you liked this episode, please leave us a rating and review on Apple Podcasts or Spotify. We really appreciate your feedback. We’d also like to thank all of our generous sponsors for their support of this episode of the Can Do MS Podcast. Until next time, be well and have a great day.

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