Science Friday - CAR-T Cell Therapy For Autoimmune Diseases | Measuring Early Life Adversity—In Marmots

Episode Date: November 13, 2024

In a Chinese study, donor CAR-T cells sent autoimmune diseases into remission. There’s hope that the therapy is scalable. And, scientists used decades of yellow-bellied marmot research to find a way to measure how adverse events affect wild animals’ survival.CAR-T Cell Therapies Show Promise For Autoimmune DiseasesFor decades, immunologists have explored CAR-T cell therapy as an effective tool to fight blood cancer. Increasingly, CAR-T cells are being explored as a potential silver bullet for treating autoimmune diseases, like lupus—which currently have no cure.Thus far, CAR-T cell therapy has largely used CRISPR-modified immune cells from a person to treat that person’s own diseases. But new research from China has made a huge step forward for this treatment: Researchers were successful in using donated CAR-T cells from one person to treat another person’s systemic sclerosis, an autoimmune condition that causes atypical growth of connective tissues.If donor CAR-T cell therapy does indeed work, as posited in this paper, it could mean the therapy is more scalable than it would be otherwise. Joining Ira to talk about this study and its potential impact is Daniel Baker, PhD student in the immunology lab of Dr. Carl June at the University of Pennsylvania.Measuring The Effects Of Early Life Adversity—In MarmotsIt’s well-established in psychology that if you experience trauma as a child, chances are it’ll impact your physical and mental health as an adult, and could even affect your economic status. In academic terms, this is called early childhood adversity. And psychologists have developed a scoring system for measuring the cumulative effect of adverse childhood experiences, which can include abuse and household dysfunction, and it can help predict health risks later in life.So we can specifically measure that in humans. But what about other animals? If you’ve adopted a dog that’s had a turbulent past, you know that that can result in reclusive or skittish behavior as an adult. But there hasn’t been a good way to measure it in wild animals.Well, a new study from UCLA, published in the journal Ecology Letters, establishes a similar index for wild animals, and it used decades of findings from a mammal: the yellow-bellied marmot. So how could it help conservation efforts for other animals?Ira Flatow talks with Xochitl Ortiz-Ross, a PhD student in ecology and evolutionary biology at UCLA, and one of the authors on that study.Transcripts for each segment will be available after the show airs on sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Autoimmune diseases have been considered incurable, but a treatment that's been successful for cancer could move the needle in the right direction. The likelihood that this could expand elsewhere is really promising depending on the safety and efficacy of carty cell therapy. It's Wednesday, November 13th, and today is Science Friday. I'm SciFRI producer Kathleen Davis. If you struggle with an autoimmune disease like lupus or multiple sclerosis, you're familiar with the the frustrations that come from not having an available cure. But there have been scattered studies that show patient progress after using car-ticell therapy. A new breakthrough shows it could be more scalable as a treatment than we've thought possible. We'll get to that story in just a bit,

but first, let's learn some lessons about stress from an unusual source. Marmits. Here's Ira Flato. It's well established in psychology that if you experience trauma as a child, chances are it'll impact your physical and mental health as an adult and could even affect your economic status. In academic terms, this is called early adversity, and psychologists have developed a scoring system for measuring the cumulative effect of early adversity in childhood, which can include abuse and household dysfunction, and it can help predict health risk. later in life. So we can specifically measure that in humans, but what about in other animals? For example, if you've adopted a dog that's had a turbulent past, you know that that can result in

reclusive or skittish behavior as an adult. But there hasn't been a good way to measure it in non-primate animals. Well, a new study from UCLA, published in the journal Ecology Letters, establishes a similar index for non-primate animals for the first time, and it uses decades of findings from a mammal, the yellow-bellied marmot, sometimes known as the giant ground squirrel. So how could it help conservation efforts for other mammals? It'll tell us more about the study as one of its authors. So Chiol Ortiz Ross, she's a doctoral student in ecology and evolutionary biology at UCLA.

Welcome to Science Friday. Thank you, Aaron. be here. Nice to have you. We know that negative childhood experiences can have an impact on human adults. Why is it important to develop a similar score or index for non-humans? Yeah, so it's important for many of the same reasons. We're interested in how cumulative adversity affects humans because we're interested in their well-being and be able to prevent the consequences of an accumulation of stressors later in life. And so with animals, we also care about their well-being. and we're particularly interested in that when we talk about conservation,

but also when we just want to have questions about their ecology and their evolution. All right, so tell me why, of all the animals you choose, why did you choose to focus on yellow-bellied marmets? I think they're a pretty big rodent that most people have never seen. Well, they're certainly adorable, but one of the major reasons why we chose yellow-bellied marmits is because they're the longest continuously running study of mammals in the world. The data that has been collected for over 60 years, and so we have a lot of knowledge

about these individuals and their ecology and life history, but also we're able to use a lot of data to quantify the cumulative impact of multiple stressors. So we had a lot of data available, is the short answer. And speaking of stress, tell us what kind of stressors they go through in the wild. Yeah, so they experience a number of different stressors, the ones that we sort of, selected can be things like the timing of spring. So arrival of spring is great because it brings in food. The grass starts to grow again after the winter. And so that's an important determinant of fitness in this population. So late spring is an adversity. Similarly, summer drought can also be adverse as well as predation pressure and other things like parental effects like did you have a stressed

stout mother, or did your mother not have a lot of mass going into the pregnancy and even losing your mother can have important consequences? And they have to deal with us humans, too, right? Absolutely. Yeah, were there any results that were surprising to you? Overall, we were hoping that we would find this decrease in survival probability with increasing adversity, which is what we found. So it was a pleasant surprise, but it was also what we were expecting or hoping to see. We also found that not all of the adversity measures had a significant impact on survival, but our index shows that the accumulation of them, like the experiencing multiple ones of them, did. So that's the main thing. Yeah. So how now that you have this index, this cumulative adversity index, how do you use it? You use it in analyses.

So a big reason why at least the impact of multiple stressors hasn't really been studied in wild populations before is because we didn't really have a good way of measuring it. And so this is just the way that you can ask those questions regarding cumulative impacts that you may not have been able to answer before. But now you can use this one number as a substitute for like a list of many different stressors. Yeah, it sounds like it could help local governments focus on specific stressors. strategies to protect these populations, especially all the stressors that people give them, light, sound, pollution, stuff like that. Absolutely. One of my biggest concerns and reasons why I started this study was because animals

around the world are experiencing these increasing stressors, especially with humans in the picture. And so my hope is that people will start to use it and consider more of the, the cumulative impact of multiple stressors when thinking about conservation. Most of the way we think about conservation action is to identify the stressor that has the highest impact and then work on trying to minimize that. While we're suggesting that it might be equally helpful, if not perhaps even more helpful, to consider maybe some of those, let's call them the lower stressors, but trying to tackle multiple ones that we might have control over things like exposure to humans.

So reducing ecotourism in a particular area, especially during the rearing of the younger individuals, we could provide greater food access during times when there is a food shortage, either due to drought or due to habitat loss. I guess my perspective is to think about them less hierarchically and more. by paying attention to this cumulative impact. So considering even those stressors that you might not think have a greater effect, small things can accumulate really quickly. And so thinking about what can we actually have an impact on,

what can we actually reduce and focusing on those instead of trying to reduce something that may be really harder and possible to do. Well, good luck to you. I want to thank you for taking time to be with us today. Thank you so much. So, Chair Ortiz-Ross, a doctoral student in ecology and evolutionary biology at UCLA. After the break, we'll talk to one scientist who thinks carty cell therapy could be a silver bullet for autoimmune disease.

CAR T cell therapy has been a very promising treatment for cancer. It uses the body's own immune system to target bad cells. And there's news from many different studies that carty cells could be used effectively now, to fight autoimmune diseases too. This is a big deal because there's no cure for many autoimmune diseases like lupus and celiac. A recent study out of China shows even more exciting possibilities for CAR-T cell therapy, a success from using donated cells from someone else.

Wow, can this therapy be scaled up for the millions who could benefit? Joining me is Daniel Baker, Immunology, Ph.D. student in the lab of Dr. Carl June, one of the pioneers of CAR T-cell therapy at the University of Pennsylvania in Philadelphia. Welcome to Science Friday. Thanks, Ira. It's great to be here. All right, let's do the ABCs. Daniel, give us a brief reminder of how carty cell therapy works. Sure. So one of the wonderful things is car T cells, though they can be very complicated from a manufacturing and a scalability standpoint, theoretically are very simple. Really, what we're trying to do is we are building a synthetic receptor that's never existed before in nature by combining the antibody domain of a B-cell

with the T-cell activation domains. Essentially, the outside of that receptor lets you see your bad cell, and the inside of that receptor activates a T-cell. And so just like you said, when a car actually sees whatever you're telling it to target, it activates your T-cell and lets you get rid of whatever that bad cell is. Wow. Wow. So it could potentially be used in all kinds of diseases. That's right. While car T-cells have shown, you know, exceptional potential in blood cancers, one of the things the field has been percolating for a number of years is could this same

strategy using a cell-based platform be useful beyond cancer? And so now we're seeing promising results treating autoimmune diseases. Tell us, how that works? What diseases are we talking about? Yeah, so diseases like systemic lupus, erythematosis, lupus nephritis, myasthenia gravis. There's actually a whole host of diseases that we do think are B-cell mediated, but where we're starting to see early indications of carty cells actually working is in these really refractory cases where patients have been on courses of treatments, some of them, you know, for decades. Right. And the question is, could something that is a little bit more potent than an immunosuppress of a small molecule or even a biologic,

like a cell therapy, could that be efficacious in those contexts? But like you've likely alluded to, Ira, and your listeners know something that's really interesting is there's a whole host of autoimmune diseases that potentially could be targeted using the same strategy going after bad B cells. Right now the field is starting in these very serious diseases where there is no alternatives. but the likelihood that this could expand elsewhere is really promising depending on the safety and efficacy of carty cell therapy. Yeah, let's get into some of that research because, as I mentioned, there was a recent study out of China that successfully used donor carty cells to treat autoimmune conditions.

What was your response to reading this paper? We think it's really remarkable because something that we think about a lot in the field that is kind of troubling for us is, you know, CARC cells are extremely powerful, and it's really a new paradigm in medicine using a patient's on cells to target disease. But one of the difficulties that we have to face as a community is if CART cells started working in a whole bunch of blood cancers and a whole bunch of solid tumors in an autoimmune disease, one of the problems we face as a field is we do not have enough capacity to treat

all the patients who could potentially use this therapy. And so one way that the cancer field has started to think about, how do we circumvent this limitation is could we, instead of using a patient's own T cells, and every single time we needed to treat a patient with car T cell therapy, we would have to take T cells from a patient and modify them in a laboratory, grow them up, and send them back to the patient? What if we could just take T cells from a healthy donor, make a giant batch of those T cells, and then infuse those into multiple patients? And so I think the most exciting part of the study from China was, you know, in three patients, they took donor cells from a healthy donor. They made carty cells, CD-19

carty cells that they modified so that it wouldn't have graft versus host disease. And they asked the question of, if we give these to autoimmune disease patients, do we see them in graft, persist, and have any functional benefit? And so really the implications potentially is, if we can get donor cells to work in an autoimmune disease setting, the likelihood that this therapy could scale out would be really remarkable. And did the they see it work in those three patients? Exactly. What was so promising about this is they saw in all three patients, the CART cells in grafts. So they looked in the blood weeks and months later and they saw CART cells there.

Then the most important question is, are the CART cells actually working? They said, are there B cells? The B cells went away for a period of time. And then they came back, the same thing that we're seeing in other autoimmune disease context with autologous CART cells. And they saw improvements in all disease contact. So the authors showed that these patients showed remission for all three different diseases, or all three different patients, rather. And that's really, really exciting. Like I mentioned, it's still early. You know, six months is not a lot of time. Autoimmune disease is complicated. But it's really promising that there's any effects being seen using donor car T cells in order to treat autoimmune disease. So this is really, I mean, three patients, this is really early stage, right?

Yeah, you're absolutely right. How do you scale this up to see if it would work? Yeah, you know, there are over 40 clinical trials that have been registered now exploring CAR T cells in autoimmune disease. So I think very quickly, we're going to start getting answers to, you know, what actually is the efficacy rate of CART cells and what does the safety look like? So I think very quickly we will get a sense on autologous CART cells because I think that's where a lot of people are focusing.

And hopefully in the next coming years we'll get a sense of whether or not allergeny or maybe even in vivo, CART cells could potentially be a therapeutic avenue for a subset of patients. You mentioned safety, of course, we're always concerned about safety first. Are there any safety drawbacks to this treatment? Yeah, I think, you know, the safety concerns are the things that need to be emphasized. You know, one of the things that we were really worried about is carty cells and cancers have, you know, a whole profile of safety concerns that we have to be

worried about, you know, this hyper-inflammatory response because your carty cells are working. They're seeing tumor and they're expanding. And so when carty cells first went into autoimmune disease patients, I think this is something that the field is really concerned about. Now, I think we still need to be mindful. There's just been a smattering of case reports and case studies that have been published. So we need phase one and phase two clinical trials to actually see what the safety and efficacy looks like. But speaking broadly, these carty cells in autoimmune disease look much safer than what we see in cancer. So, most patients have less than grade three cytokine release syndrome. I know that there's been one report of

a neurotoxicity, but again, that is a much smaller safety profile than what we have seen in cancer. And so really what is particularly exciting for us is it looks like a lot of the safety concerns are maybe a little less pronounced in a nanoimmune disease setting. And that's something that we thought might be the case. In cancer, you have millions, billions of cells that are rapidly proliferating that you're trying to get rid of. In autoimmune disease, you don't have this, you know, huge target burden. And so your carty cells don't need to kill as many cells. And we thought that that potentially might be the case that you wouldn't see as strong

safety effects. And that's, you know, being borne out and time will tell how long that is true. But we'll see. Right. Any tests planned here for the U.S.? Yeah, I think there's a number of clinical trials that people are trying to get going in the United States. I think trying to expand this to multiple different countries.

You know, a lot of the pioneering work has been done in Germany. And as you've mentioned, there's a lot of work being done in China. But I think expanding it to the United States is something that we're really excited about doing. So what could this mean then for the future of medicine if we're able to scale donor carty cell treatments? Well, at the risk of being hyperbolic, I really do think cell therapy could change everything. I think it could change medicine as a whole. It's easy to think of carty cells, and I think lots of us think of carty cells. as kind of an iterative next step.

You know, it's a living drug. But I think what we have done for the first time is we have taken, you know, the fundamental unit of life a cell and used it to treat disease. And so the implications for cancer and for autoimmune disease now seem clear. I think that carty cells in autoimmune disease

definitely has a future. But like you've mentioned, the host of promise for other diseases is really exciting. You know, there's some pioneering work that's being done by John Epstein's group here at Penn. showing that you could use carty cells to go after scar tissue in the heart after a heart attack. And at least in mice, we see really, really strong and promising effects. The same thing is true with chronic diseases in senescent cells.

I think really there's a whole host of diseases that potentially could be actionable using a cell-based platform. Using cells, you know, we often talk about cellular therapy as a new pillar in oncology. But I think really what we are facing in this decade is that cellular therapy is going to be a new pillar of modern medicine. And what exactly that looks like is going to be fun to explore in the next coming years. Are we talking about cures here instead of treatments? Because I'm wondering if you think as a young researcher in medicine about a dilemma we have had researchers on the show who talk about carty cell therapies as being so promising they could cure diseases. And the dilemma being, is it in the interest of drug companies to cure diseases?

Right? when their stockholders expect them to maximize profits, which means a cure, not a cure, but, you know, let's have them taking drugs forever. Yeah. Yeah, I think I understand the economic implications for some of these companies. But at the end of the day, they're trying to capture value to. And I do think that these will be cures, at least in a subset of patients. It's clear from cancer that's the case, whether that will be true in autoimmune disease.

only time will tell, obviously. But I do think that cellular therapy has the potential because it is a living drug is something that could be curative in a whole host of disease settings. And I think that ultimately, that could change medicine. And whether that will have implications economically, it surely will. And I think we are pretty dynamic as a society. And I think we'll respond appropriately to the promise of a new era in medicine. Daniel, I thank you for taking time. This has been tremendously uplifting, I think, at a time when we need something like that. Thanks, Ira. It's been great to be here. Daniel Baker, Immunology PhD student in the lab of Dr. Carl June, one of the pioneers of

CAR-T cell therapy that's at the University of Pennsylvania in Philadelphia. That's all the time that we have for now. A lot of folks help make the show happen, including Sandy Roberts. Beth Rami. John Dancosky. Annie Nero. And many more. Tomorrow, we'll revisit a conversation Ira had with the incredible Oliver Sacks about how the brain processes music. But for now, I'm sci-frey producer Kathleen Davis. Take care of yourselves.