← MS Living Well: Key Info from Multiple Sclerosis Experts
MS Living Well: Key Info from Multiple Sclerosis Experts
Reengineering Hope: CAR-T Therapy for Multiple Sclerosis
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- [00:02]
A
Greetings all. Welcome Back to the Ms. Living well podcast. I'm your host, Dr. Barry Singer, director of the Ms. Center for Innovations in Care at Missouri Baptist Medical center in St. Louis. Today's episode is Re Engineering Car T Therapy for Multiple Sclerosis. This episode is sponsored by TG Therapeutics. CAR T therapy is one of the most exciting frontiers in the search for new Ms. Treatments already transforming care for certain leukemias and lymphomas. This approach takes a person's own T cells, RE engineers them in the lab to recognize a specific target and RE infuses them to track down and eliminate harmful cells. Now researchers are asking, could, could this same technology be directed against immune cells that attack myelin and multiple sclerosis? Unlike many Ms. Therapies that require ongoing treatment, CAR T is being studied as a one time infusion that might provide long lasting effects. Later on in the show, we'll speak with Dr. Amanda Piquet about potential risk of CAR T treatment and how this technology is beginning to expand into autoimmune neurology conditions more broadly. But first, I'd like to introduce Dr. Jeff Dunn. Dr. Dunn is the Lily Seraphin Director of Neuroimmunology and serves as Clinical professor and Chief of Neuroimmunology in the Department of Neurology and Neurological Sciences at Stanford University. He has served as principal investigator in more than 30 clinical research trials, authored numerous scientific publications, and is a multiple time recipient of neurology residency teaching awards. Dr. John, wonderful to have you on the Ms. Living well podcast.
- [01:50]
B
It's a great honor to be with you, Barry. Thank you so very much for the invitation and I'm delighted to be here and talk about this really exciting subject.
- [01:57]
A
Awesome, Jeff. So let's start with the basics. What is CAR T therapy?
- [02:02]
B
CAR T is an acronym. It stands for chimeric antigen receptor therapy. That's a mouthful. So to keep it simple, people can imagine their immune systems as their own personal, military or or secret Service. The immune system protects us against infection. And just like the military, the immune system has different branches, different effector arms that have different functions. Lymphocytes are cells that I suspect everyone has heard of. And there are two major subtypes, B and T lymphocytes. Each of them has a different role. One is a search lymphocyte and the other is a destroy lymphocyte. What CAR T therapy does is it brings those two things together. So a CAR T cell is a really highly specialized, designed, engineered cell that has search and destroy functions altogether.
- [02:58]
A
So how Is this engineered? What do you mean by that?
- [03:01]
B
That's a living medicine. So it's different than something synthesized chemically. CAR T cells are derived from in two ways, but they're human T cells, they're human T lymphocytes. The more common way T cells are made is by collecting large amounts of the patient's own T cells and then engineering them, often with a retrovirus, so that the patient's own T cell begins to express a B cell receptor, like an antibody receptor, that allows it to target a very specific antigen or protein.
- [03:34]
A
So it's basically you take this T cell and you're infecting it with a virus. Right. So the virus contains a gene and that creates something on the surface of the T cell that wasn't there before. Right?
- [03:47]
B
That's well said.
- [03:48]
A
So it's basically like a receptor and that has a specific target. Right. So now the T cells can go after something specific.
- [03:56]
B
That's exactly right. So T cells recognize whatever you tell it to. The process is called transduction, and it confers T cells with a high degree of specificity. So it gives us in treatment, the chance to combine a specific target and minimize off target effects, which ideally would minimize side effects.
- [04:17]
A
So you're basically making these designer T cells your own T cells, but having them target something specific. And in ms, we're going after what.
- [04:25]
B
So far, B cells. So as you may know, CAR T cells, they were originally designed for HIV success, but then they were used for different hematologic malignancies, like lymphoma, with sometimes miraculous success, often led by our colleagues. Then at Penn, there are, to my knowledge, six presently FDA approved commercially available CAR T cells that are all used for hematologic malignancies. And four of the six of those specifically recognize a protein expressed on the surface of cells called CD19. CD19 is a protein expressed specifically on the surface of B cells. And in our early work, we're using CAR T cells that target that. So we target B cells very specifically in this therapy.
- [05:18]
A
And CD19, though, is also on the surface. Not only B cells, but plasma cells and plasma cells make antibodies, right?
- [05:24]
B
Yeah, that's right. CD 19 is broader. Your listeners should know that B cells undergo a series of maturation steps from essentially a null cell in the marrow. And as you made mention of, the final differentiation of the B cell is the plasma cell which produces antibodies. CD19 is expressed on a broader array of that spectrum, and so it potentially could be a bigger effect, maybe with potentially a greater risk of lower antibody levels.
- [05:58]
A
Right. The CAR T is going to go after not only the B cells, but the plasma cells. We already have antibody therapies that knock out B cells. So we think of these drugs like Ocrevus and key symptom brieonv. Is there any advantage of doing this with the designer CAR T cell versus just our traditional antibody therapies?
- [06:20]
B
That's a great question. And it gets to what might be the biggest advantage of this potential immunotherapy. There's great strong evidence of how effective CD20 monoclonal antibody therapy can be for the patient with Ms. The problem is that antibodies are really big molecules and they don't effectively cross the blood brain barrier. So they can be given either as IV infusions or one formulation is as a subcutaneous injection monthly, as you know. But those molecules will work in the periphery. They're very effective in depleting B cells that express the CD20 glycoprotein. But in what limited studies have been done, there's virtually none of that molecule that can actually cross over into the central nervous system. And CAR T therapies can, because their basic foundational structure is the patient's own T cell. They circulate widely throughout the body, including the sanctuary sites of the central nervous system, the secondary lymphoid tissue, such as lymph nodes and tertiary lymphoid follicles. They have the ability to offer deep tissue penetration for Ms. Specifically, there's a reason to think that central nervous system penetration and central nervous system action can offer very distinct and advanced therapeutic advantages.
- [07:43]
A
Right. So particularly when we think about progressive ms, there are clusters of B cells, we call them follicles, in the coverings of brain and spinal cord, which is called meninges. So the idea would be maybe going after these B cells may play a role in progressive Ms. That's spot on.
- [08:01]
B
Yes. So a number of studies, and I think with some consistency that should be reassuring to us, have shown that in patients with progressive types of ms, the folks that are experiencing worsening, increasing weakness even in the absence of relapse, there appears to be a greater association with these meningeal B cell follicles that you just made reference to. They've been seen in a number of different ways, but they do seem to cluster into follicles in the meninges within the central nervous system. So if we say to ourselves, these meningeal B cell follicles are contributing to the disease, they're not being treated by the peripherally given CD20 therapies we presently have available. But they might potentially be very effectively treated and lysed by CAR T therapies because of that penetration into this sanctuary side of the central nervous system.
- [08:59]
A
If a patient's out there interested in CAR T, you mentioned, first of all, you got to get the patient's T cells out. How do you get all these T cells out so they can be re engineered?
- [09:10]
B
So CAR T therapy can be autologous, which means based on cells that are collected from the patient. And that's what I'll speak to now. But I do want to introduce the idea that there are some early plans to create allogeneic CAR T cells which are given by donors. If we use an autologous process, what we do is we identify the patient, we screen to make sure there are not latent infections and that collection of their own blood by this process is safe. We then put them through this apheresis process where a relatively large bore catheter is put into their vein. Feels almost a little bit like dialysis where blood is drawn out of that catheter. Their own red blood cells and their own plasma are immediately returned to them. But T cells are spun and then collected so that we can collect their own T cells by this process. Post collection handling can be very sophisticated. But we'll take the patient's T cells and then work with one of these specialized laboratories to transduce them, which is the process by which we bring that new gene into the patient's T cells so their T cells can express this B cell receptor and then amplify their numbers so that the cells can be given as often a single infusion.
- [10:32]
A
And where's this catheter place?
- [10:34]
B
It can be an arm vein.
- [10:35]
A
By your elbow.
- [10:36]
B
By your elbow. Well said. But there are some people who don't have great big thick veins. Veins. And in those cases, we can use a temporary central venous catheter. And that would be placing a catheter often below the clavicle to collect blood from the bigger vein there. It's usually one side or the other.
- [10:55]
A
So this is a few hours that you would be there while they're collecting the cells.
- [10:59]
B
Exactly. The whole process of insertion collection centrifuge takes about three to six hours. And it's on one occasion.
- [11:07]
A
So then it goes off to the lab. It goes through these steps. Proliferation. You know, you're trying to grow up the amount of cells and infect them with the virus. It's going to make this new receptor on the surface of the T cells. And how long does it take to get it back from the lab that's doing this work.
- [11:24]
B
Yeah. So this is really complex, advanced work, and it's still relatively new. The answer to your question, I would say is about four weeks. There's a great interest in this as emerging therapy, not just for Ms. But for other related diseases like autoimmune diseases. So active efforts are being made to try to shorten the amount of time it takes between collection of blood and then the availability of CAR T cells for infusion. But it does take about four weeks. That's one of the potential drawbacks to this autologous process, and we're trying to speed that up as best we can, but you can't hurry these things too much.
- [12:02]
A
Yeah. And the process happens in university settings. They do it as well. Or is it all private labs that do this?
- [12:08]
B
To my knowledge, we've worked with private labs. We often work collaboratively with a group that's outside our university to do this.
- [12:16]
A
So, Jeff, now we're at the point where the CAR T cells have been made and ready to introduce into the person, and we're talking about Ms. So someone living with multiple scrotuses. So what needs to happen in order to infuse these cells back in?
- [12:32]
B
We have to make room for the cells. If we collect these cells autologously, meaning the patient's own cells, those, of course, are going to be recognized by the patient as self. But remember, we just introduced a receptor on these cells that the body won't recognize completely as self. And so we use a lymphodepletion regiment, which is low grade chemotherapy. The most common lymphodepleting regimen that's used is a combination of cyclophosphamide and fludarabine, which can cause sort of chemo like side effects, it can reduce cells, it can make people nauseated. In the trial that we're doing now, we've used one that is more mild, that we hope will be better tolerated and less associated with side effects, called bendamusti. But to answer your question directly, if a patient appears stable, clear, free of infection, ready for their infusion, they come in often five days before their planned infusion, and they're given a regimen of either what's called cy flu, cyclophosphamide plus fludarabine or bendamustine, usually beginning five days before the infusion, over a period of between two to three days, and then.
- [13:48]
A
They'Re ready for the cells.
- [13:49]
B
So on day zero, five days after the initial treatment, they receive a single infusion of their own CAR T cells that have been engineered to express this B cell receptor, like we've talked about. I have to tell you, Barry, it's remarkable how anticlimactic the infusion of CAR T cells actually is, no matter what the number. And the most common number that's infused is 100 million cells at one time. It's given as a 10cc IV push over no more than 10 minutes time.
- [14:20]
A
Wow.
- [14:21]
B
The patient themselves can often think this is going to be a big dramatic moment. I mean, how could you not think that as a patient? And yet the infusion, it's surprisingly simple.
- [14:31]
A
But they don't get in the car and drive home after this, right?
- [14:35]
B
Not at all. So because this is such a brand new study and it's not been used for multiple sclerosis before, our very first solemn responsibility is to assure safety. And so the study protocol we're using in this clinical trial demands that the patient stay in the hospital for a period of no less than seven days after the infusion, sometimes 10 days. There are protocols being discussed that say the patient must be there on site for two weeks. And the reason for that is because they can have side effects and potentially serious side effects following this infusion as these cells are identified and lysed.
- [15:15]
A
Jeff? Yeah. We're going to get into the potential complications in just a few minutes with Dr. Piquet. In the meantime, can you tell us what your patients have thought about the process so far?
- [15:25]
B
I should salute the bravery of the patients first, because they have agreed to step forward and do something that we don't have great evidence for. I have to say, the patient experience a little bit with a grain of salt because our numbers are few. We've only enrolled six patients to date, although certainly we plan to enroll more. Patients generally have tolerated these infusions well. Often, though, about 10 days after the infusion, on average, they can develop a very abrupt onset of fever. It hits them very quickly, unlike getting a community acquired virus. All of a sudden, boom. They go from normal to feeling febrile, having a temperature of 100, 101, all of a sudden. And we know that corresponds to the CAR T cells expanding within their body. So once those CAR T cells recognize their target, they're trained to proliferate, to grow in number, and to go on the attack. The human body experiences that as fever, a pro inflammatory phenomenon to help those cells grow. With ms, though, fever can make Ms. Patients feel weaker, and we've seen that in every occasion so far that it tends to pass and respond to hydration. And acetaminophen, relatively simple therapies in our experience. In limited numbers, we often can help people get through the fever. In a couple of days, they begin to get their strength back. We have not seen a true new Ms. Exacerbation in our experience so far.
- [16:59]
A
So do you have any data yet on if the treatment is working?
- [17:03]
B
Yeah, we sure do. So we've looked very closely. There are some central questions here, as you well know. The first is, if we do give an infusion of these CAR T cells, do they get in and do they proliferate? Do they expand as we expect them to? And in every case so far, I'm happy to say the answer is yes. Actually, we've seen really robust proliferation where these cells have increase, increased into the millions. The second question, based on our previous conversations, is do these cells actually get into the central nervous system? And our patients, much to their credit, have allowed us to do three spinal taps within a six month period. We've looked at their cerebral spinal fluid at baseline before treatment. We look at it again in two weeks after their therapy to ask the question, do these CAR T cells get into their central nervous system? And the answer is yes, in every case, we've seen really very robust expansion and penetration into the central nervous system. And then we check again with their CSF at 6 months. I should back up and say it looks as if the CAR T cells themselves tend to disappear or drop down to zero or very close to zero about 28 days after their infusion. So that's favorable. And at six months, we've seen some remarkable things. In one case, a patient who had oligoclonal bands at baseline had those bands disappear in association with this therapy.
- [18:39]
A
And these are the antibodies in the spinal fluid that we look for to diagnose ms?
- [18:43]
B
Yes, that's right. They suggest that the immune system is recognizing something there that's foreign. And it's in a way the hallmark finding of multiple sclerosis. We see it in more than 95% of patients. In other patients, we haven't always seen a complete eradication of those oligoclonal bands, but we've seen a slight decrease. We don't know what that means yet, but there does look like there's an immune effect.
- [19:08]
A
Do you think it's because we're knocking out the B cells or are we also knocking out plasma cells in the spinal fluid that are making the antibodies?
- [19:15]
B
I think it's the B cells. Now, this is theoretical. I really want to stress that because I don't want to say things that we don't have evidence of. But my sense of this is that we know that there's an association with multiple sclerosis and Epstein Barr virus. Epstein Barr virus lives within memory B cells. About 1 out of every 10,000 B cells harbors Epstein Barr. For those people who have been exposed, and that's most people, there are more factors involved in causing Ms. Than just Epstein Barr virus exposure. But I think this therapy is eliminating those cells that are infected and by its mechanism, it's driving those memory B cells out of the system and out of the central nervous system. We then see that the B cells will regrow, which is wonderful, but they're growing back with what's called a naive phenotype. They're growing back from scratch, from the marrow without that infection, without that EBV Epstein Barr virus pollution. And that introduces the idea that maybe this therapy provides a true immune reset for patients with multiple sclerosis.
- [20:29]
A
Now, do you think this is going to be a one time process? One and done?
- [20:32]
B
One of the great advantages of CAR T therapy would be theoretically it could be one and done for just the reasons I mentioned. If it truly eliminates the B cells that might be driving the Ms. Process and then B cells are reconstituting from scratch and fresh, a true immune reset, then the process that's driving Ms. Has been eradicated. So theoretically this may be a one and done process. And that has potential advantages. Patients may not require long term recurrent immunotherapy that they often now need to keep their disease optimized. There are potential complications with long term therapy that may be reduced. There are substantial costs, as any patient will know when they see the cost of their therapy, that if we could reduce treatment to A1 and done in the long run, that may also be medically, economically advantageous, but more importantly, therapeutically advantageous for the patient who's treated.
- [21:36]
A
So how can someone get involved if they're interested in participating in CAR T research and are there specific patients that are being recruited for these studies?
- [21:47]
B
So if a patient asks their Ms. Specialist, their Ms. Specialist is going to know what's happening. Because this is a very exciting topic within our field right now, One of the most exciting one that's getting a lot of attention, as I think it should. A second way is to look@clinicaltrials.gov which is a website which is very thorough and very up to date, that lists the trials that are ongoing and provides their status. Are they active, are they recruiting? Is there a site within one's own community that might be convenient. I do have to say this is brand new. We're really just beginning. There are only a couple of sites at this point that are doing this kind of work. And most of the trials being done right now are in their very first phase, Phase one, which really focuses on safety and feasibility in your trial.
- [22:42]
A
At your side, are you looking at more relapsing patients or more secondary progressive patients?
- [22:47]
B
We're looking at progressive patients who have not responded to therapy that's already available. It was appropriate ethically, and the fda, in fact, insisted that we look to a cohort that couldn't take advantage of FDA approved therapies. And that was in people who were getting worse in the absence of relapse, who hadn't responded to therapy that might have otherwise been indicated. I have to say that if this works as well as we hope it might, our indications might expand.
- [23:19]
A
So, Jeff, how optimistic are you about CAR T therapy?
- [23:22]
B
Do I have permission to speak informally?
- [23:25]
A
Yes. This is informal. This is. You're on a podcast.
- [23:28]
B
I have never been more excited about a therapy than this one. Never. This is only personal opinion because we don't know the cause of Ms. In 2025 and we don't have a cure. But I think Car T therapy in Ms. Is uniquely well tailored to what drives the Ms. Process. I can't even imagine that I'm using this verb, but I'm going to. I think there's a chance that this process could eradicate the Ms. Process in individuals, that it could truly provide an immune reset and cleanse them of this autoimmunity that's driving their disease.
- [24:07]
A
That's truly amazing. So what have you seen so far?
- [24:11]
B
Yes. You know, in a phase one study, you don't really expect to see too much clinical benefit, especially when you're pre selecting patients who have had Ms. For 10 or 20 years and are getting slowly worse and are not having relapses by definition. And yet what we've seen is first, after the infusion, after patients have felt often lousy, if I could be candid, they can feel lousy for about three months. But then after that three months, every one of them has enjoyed this remarkable improvement in energy. Right. Fatigue is the most common symptom associated with Ms. And these patients come back to us and say the fatigue that they had felt, it seems as if it's just lifted. What they describe to us in their daily living is they're living like they used to years ago, even before their diagnosis, and they're not experiencing that Ms. Related fatigue. We've tried to measure that as well as we can with modified fatigue impact scales and patient reported outcomes. And we're seeing 8 to 10 point differences for the better in every patient that's been treated to date. You know that that's exceptional. I mean, I have never seen that in all my years of practice. Will we continue to see that? I hope so. The numbers are too small for me to make a conclusion, but it certainly gets my attention. The other thing that we've seen, amazingly, is an improvement in EDSS of between 1 to as many as 2.5 points in patients where disability is often established.
- [25:52]
A
And then for our audience, EDSS is a 10 point scale looking at disability. The higher the number, the worse that they do.
- [25:59]
B
Yeah. Thank you. These patients are saying that they can do things now that they haven't been able to do for a while. We had one man as an example who was able to stand and take a couple of steps, such as making a transfer from his wheelchair to his commode at home, who now is able to stand and walk with assistance, but walk the distance of a football field. And he hasn't been able to do that for 10 to 15 years.
- [26:21]
A
Holy mackerel. That's amazing.
- [26:23]
B
We had a woman who, when she would take her family to Disneyland, which was a favorite of theirs, she'd have to go in a wheelchair or need assistance. The last time she went after treatment, she was able to walk around the park for 13 hours. She didn't even use the disability lines for the rides. She said she felt connected with her family in a very special way, as she'd hoped for.
- [26:47]
A
That's spectacular. I mean, is this repair. Some people have numerous lesions on the brain and spinal cord.
- [26:53]
B
I don't know. It's very important for your listeners to know that what I'm describing are very small numbers. And so we need to see if this trend continues. It needs to be other investigators, other sites in different parts of the country and different parts of the world to see if there's a consistency, if others are seeing the same things that we've seen. I do think what can be said though, is we must continue to pay attention to safety. But if we continue to see that there's a therapeutic benefit of this magnitude, then these studies should proceed from phase one where they are now, and really proceed to phase two and phase three and consideration of if this is something that should be developed for the Ms. Patient.
- [27:37]
A
That's amazing. So really phenomenal work. Thank you so much, Dr. Dunn, for sharing all your insights on CAR T therapy and really appreciate your leadership in the Ms. Community and all the work you're doing there for Stanford. That's really going to make a difference across a broader global Ms. Community.
- [27:56]
B
Thank you so much, Barry. It's a great privilege to be with you today. Thank you.
- [28:05]
A
I'd like to introduce you to my next guest, Dr. Amanda McKay, who is a professor of neurology and the Celine Dion Foundation Endowed Chair at the University of Colorado, where she directs the autoimmune neurology program. She received her medical degree from Penn State University College of Medicine and completed neurology residency at Harvard. She pursued fellowship training in autoimmune neurology and neuroimmunology at the University of Utah. Dr. Paquet, welcome to the Ms. Living well podcast.
- [28:33]
C
Thank you for having me.
- [28:35]
A
So, Amanda, we know that CAR T has been used in the treatment of certain types of cancers with great success. And we spoke with Dr. Dunn about its potential for treating Ms. Can you tell us, are there other neurologic autoimmune diseases that have been treated with CAR T beyond ms?
- [28:51]
C
There are other autoimmune neurologic diseases being explored. This includes autoimmune or rheumatologic diseases such as lupus. And in the neurology space, one disease that's near and dear to my heart is stiff person syndrome. We have a phase two study called Kaiser 8 that's looking at CAR T treatment in stiff person syndrome. And we actually just completed enrollment for this clinical trial, projected to have results sometime probably in the first half of next year. And so I think that's really going to pave the road for other autoimmune neurologic diseases as well. Once we have those results. There's also ongoing phase 2 and phase 3 clinical trials and other autoimmune neurologic disease beyond stiff person syndrome. So including Ms. And another neurologic condition called myasthenia gravis. Beyond the clinical trials that I just talked about, there's also case reports in various conditions, for example, neuromyelitis, optica spectrum disorder or nmosd autoimmune encephalitis, and also case reports in stiff person syndrome as well. The data is still very early, but some of the responses that we've seen in those case reports have been quite striking. Patients are experiencing improvements. Obviously, we need these larger controlled clinical trials like the one that I mentioned, and they're underway.
- [30:23]
A
Oh, that's fascinating. Can you just explain to our audience, they may not know what stiff person.
- [30:28]
C
Syndrome is Stiff person syndrome is a progressive autoimmune neurologic disease that causes muscle spasms, which can be painful, and stiffness that impairs an individual's ability to move, particularly with walking.
- [30:44]
A
Did a recent episode on bone marrow transplant. So, hematopoietic stem cell transplant. And also looking at stem cells, how you think about CAR T in terms of resetting the immune system, is it similar to that or different mechanism?
- [31:00]
C
So it's similar intent, but different in execution. So stem cell transplant uses chemotherapy to completely ablate the immune system. So when we talk about the adaptive immune system, B cells and T cells, you're really wiping it all out and rebuilding it from scratch. Whereas in CAR T is a bit more targeted. It selectively removes those specific immune cells, for instance, those B cells, without wiping out the entire immune system. So it makes it safer with less severe side effects and still offering that immune reset.
- [31:38]
A
Excellent. So let's go over some of those risks. So there are a few very specific risks for CAR T, and one's called cytokine release syndrome, or crs. So what are the most common symptoms someone should be aware of?
- [31:51]
C
So crs, as you said, is probably one of the most common side effects that we see. It's caused by this surge of cytokines, which are basically immune signaling proteins. And it occurs when the CAR T cells become activated after they're given back to a patient and we start to have this death and destruction of those people. B cells, what that looks like for patients. And just to take a step back, many patients, depending on the protocol and the clinical trial, but standard is when you get your cells back, you're staying in the hospital for a certain length of time, typically around 10 days. And patients are being monitored while they're in that inpatient setting for fever, for low blood pressure, for any difficulty breathing or oxygen requirement. Really, the first sign of CRS is developing a fever. And so if we monitor very closely and treat right away, these side effects are generally fairly manageable. And we'll use things like steroids and if needed, escalate to medications like tocilizumab, which blocks IL6, which is a certain type of cytokine. It's important to recognize, too, that CRS is likely not as severe and more manageable in autoimmune disease when you compare it to the cancer population. But obviously that's being monitored very closely in our clinical trials.
- [33:20]
A
Yeah, well, we're going to have less B cells, right? Less B cells being killed than someone that has a B cell Lymphoma has huge B cell counts, so probably less reaction. Absolutely. And we do see that with the monoclonal antibodies. Right, right. And we tend to see it pretty briefly, and it usually is during your infusion or then maybe the next day. But this can last how long car.
- [33:39]
C
T Typically, the peak is usually within the first 10 days, but that peak is somewhere between 3 to 5 days. The CRS and does it take a.
- [33:49]
A
Little while for the B cells to be knocked out? How fast do you see B cell depletion happening after CAR T?
- [33:55]
C
Oh, that's a great question. It actually works pretty darn quick. But that's something that we're monitoring within the clinical trial when we do frequent blood work during a patient's stay in the hospital, where we're actually monitoring how many B cells are there. When do you see that white cell count come down and what does that T cell expansion look like? And that's usually within days.
- [34:20]
A
Another serious complication is icans, which stands for immune effector cell associated neurotoxicity. So can you explain what ICANS is and how it's managed?
- [34:32]
C
So ICANS can present with confusion, difficulty speaking, sometimes difficulty writing. That's how we track it in the hospital. Or in extreme cases, can result in seizures. In most cases, this is temporary. This is reversible with steroids, but it does require close monitoring. Interestingly, just like crs, the incidence of ICANS appears to be lower in the autoimmune disease patients compared to the cancer patients. And that's likely differences in the disease biology, even the T cell expansion. We also learned from the cancer world because this has been going on for, like I said, almost a decade in the cancer population that if you treat CRS quickly and aggressively, you may be able to minimize the risk of developing ICANs. Because it does appear that patients who develop CRS are at higher risk of developing ICANs.
- [35:39]
A
Do we understand why people have seizures and confusion with icans? I mean, why this happens after CAR T?
- [35:46]
C
It has to do with cerebral swelling that we see in the brain.
- [35:50]
A
Got it. And that's why steroids work, huh?
- [35:52]
C
Exactly. It's probably driven by the inflammatory cytokine process, which is why we see this occurring in patients that had crs.
- [36:02]
A
Is this treat with oral steroids or high dose iv, IV steroids? Well, fortunately, our Ms. Patients are.
- [36:08]
C
They're used to that.
- [36:09]
A
Everybody living out with ms, you guys all know about the steroids? Not always. Our friend, little insomnia, little blood sugar issues, but a serious condition that responds to. It's Great. And then I assume if you have seizures, then you start anticonvulsive medications like Keppra.
- [36:21]
C
Yeah. And many protocols actually right now will put patients in the first 28 days where that risk of ICANS is highest. We'll put patients on a seizure medicine as a prophylactic agent to help prevent that side effect of icans.
- [36:38]
A
So what about serious infections or low blood counts that we call cytopenias? How much of an issue is that?
- [36:46]
C
So the way CAR T works is clearing out those B cells. Those B cells are a type of white blood cell, so it's expected that we see a drop in blood count. Because of that, there is this risk of infections. Patients will be monitored, like I said, closely in the hospital for the first, usually couple of weeks. And then most protocols in research right now require patients to stay within a certain radius from the medical center. So I do tell patients to be careful, particularly in those first 28 days. You are immune compromised. You are at risk for developing infections. So we want to be thoughtful and careful.
- [37:30]
A
Do you have to start people on prophylactic antibiotics or antiviral medications during this period of time?
- [37:36]
C
Yes, there is a protocol in place for that as well. Patients get antivirals sometimes up to a year. There's also antibiotics that patients will get, and that's usually prescribed by our hematology team. And the first 28 days are different antibiotics than later on. And so it really. Monitoring those counts and following whatever that protocol is. There are various antibiotics and antivirals that are taken.
- [38:05]
A
Good. That's important to know. You're in Colorado, I'm in Missouri. So we have a lot of rural patients. So what do you do if they have to be an hour away from the medical center and they live three hours away and, you know, limited hospitals?
- [38:17]
C
That's a great question. And I think. I think those protocols perhaps will have to be well thought out when this is a commercially available therapy right now, because it's being done as a research protocol. We're fortunate enough to have that funding. Where patients are staying in a hotel nearby at our site.
- [38:40]
A
Yeah, yeah. So that'll be important, and we'll need to think about that. Is there concern about the risk of developing cancer after CAR T?
- [38:48]
C
This is something we have to monitor carefully. We don't have a full, clear picture yet here of this long term risk. You have to remember, CAR T was developed to treat cancer in the first place. So any secondary cancers that we see in a cancer patient after CAR T is difficult to interpret. How this is going to look in comparison to the autoimmune patient. However, any therapy that manipulates the immune system raises that theoretical concern. So long term safety tracking is going to be essential. And for many studies like the one that we're running here in Stepperson syndrome, there's an FDA requirement to follow these patients up to 15 years after Car T to really understand that risk.
- [39:37]
A
Are there any other strategies done to reduce these risks for autoimmune patients getting CAR T? So you mentioned prophylactic antibiotics. Prophylactic, maybe seizure medications. Are there other things that you guys are working on?
- [39:50]
C
Some patients will get something called a low igg or hypogamma globinemia, something that we can see with our monoclonal antibodies as well. And we will use agents like IVIG to help supplement the immune system system if needed.
- [40:06]
A
Do you usually do this in the kind of hospital setting like on an oncology floor, or are the neurologists getting savvy enough to do this on their own?
- [40:15]
C
The CAR T treatment? Yeah, that's with our bone marrow transplant colleagues on the hematology floor.
- [40:21]
A
And then you consult for the icans?
- [40:23]
C
Yeah, we consult. And for the clinical trials, the neurologists will follow along with the patient every day, along with the hematologist. It's really a multi, multidisciplinary approach.
- [40:34]
A
So you've got to pick your center carefully as this goes forward. Yes, yes, Very, very important. What about quality of life and symptom improvement of your patients that have gone through this process? Is there something beyond just stabilizing their disease and preventing things from getting worse?
- [40:51]
C
We still need more data to really, truly answer that. However, patients have reported reported improvements, and this is in various case reports with different autoimmune neurologic disease. Reductions in fatigue, improved mental clarity, decreased pain, and even some regain in function, which is not typically our mantra when we talk about implementing immune therapies. But this is something that is incredibly encouraging, but needs to be to be studied more.
- [41:25]
A
So any final reflections or advice based on your experience with CAR T and neurologic disease, you want to share with our Ms. Community as we engage in CAR T therapy going forward?
- [41:36]
C
I'd say we're at the very beginning of a paradigm shift. CAR T isn't ready for widespread use yet, and it's not going to be the right fit for every patient. But it really does open a door that didn't exist before. For the treatment of autoimmune disease and patients with aggressive or treatment refractory Ms. Especially. This may be a great option in the future. And I would say stay engaged, ask questions, consider participating in a clinical trial if it's appropriate, and that's how we're going to move the field forward together.
- [42:14]
A
Oh, that's awesome.
- [42:15]
B
Awesome.
- [42:16]
A
Well, thank you very much, Dr. Paquet, for all your leadership in the world of CAR T and for sharing your insights with the EMS community.
- [42:23]
C
Thank you again for having me.
- [42:30]
A
Thanks to our listeners for downloading this episode of the Ms. Living well Podcast re Engineering CAR T Therapy for Multiple Sclerosis A big thanks to Dr. Zone Dunn and PKA for guiding us through the emerging role of CAR T therapy in multiple sclerosis. Early studies suggest this innovative approach may uniquely eliminate B cells within the brain and spinal cord, offering the possibility of altering the course of the disease. While there are real risks and much more to learn, the first results are very encouraging and provide real hope for the future. Thanks additionally again to TG Therapeutics for sponsoring this episode. Keep in mind the topics we discussed on the show are strictly informational and not medical advice. Any change in your treatment should be discussed directly with your healthcare providers first. Our show is hosted by me, Dr. Barry Singer and Dr. Jamie Holloman and produced by Kerriette Harmon. Our theme music is the Gold Lining by Broke for Free. If you like the show, please please share it with others living with multiple sclerosis. Also, I really appreciate a positive review on Apple Podcasts. It really helps more people find out about the show. You can follow me on X R Barry Singer and Dr. JamieHelleman BrainBoyNeuro. 1. More information about our guests and their websites can be found in the show notes for this episode and the blog section on mslivingwell.org thanks so much for listening. Listening. This has been an Ms. Slipping Whale podcast.