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

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.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Flora Lichtman?

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• 0:46Speaker 01

  WNYC is supported by Bayer. Science is about asking questions, testing, trying again. It's not easy, but it's relentless. It evolves, and that's why science delivers. Learn more at scienddelivers.com.

• 1:00Ira Flatow?

  Science Friday is supported by MathWorks, creator of MATLAB and Simulink software for technical computing and model-based design. MathWorks, accelerating the pace of discovery in engineering and science. Learn more at mathworks.com.

• 1:20Speaker 03

  Autoimmune diseases have been considered incurable, but a treatment that's been successful for cancer could move the needle in the right direction.

• 1:30Speaker 04

  The likelihood that this could expand elsewhere is really promising, depending on the safety and efficacy of CAR T-cell therapy.

• 1:36Speaker 03

  It's Wednesday, November 13, and today is Science Friday.

• 1:44Speaker 03

  I'm SciFri producer Kathleen Davis. If you struggle with an autoimmune disease like lupus or multiple sclerosis, you're familiar with the frustrations that come from not having an available cure. But there have been scattered studies that show patient progress after using CAR T-cell 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: marmots. Here's Ira Flatow.

• 2:18Ira Flatow?

  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 risks 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,

• 2:59Ira Flatow?

  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, Sochi Lortiz Ross. She's a doctoral student in ecology and evolutionary biology at UCLA. Welcome to Science Friday.

• 3:42Speaker 05

  Thank you, Aaron. Nice to be here.

• 3:44Ira Flatow?

  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?

• 3:55Speaker 05

  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.

• 4:22Ira Flatow?

  All right, so tell me why, of all the animals you choose, why did you choose to focus on yellow-bellied marmots? I think, you know, they're a pretty big rodent that most people have never seen.

• 4:33Speaker 05

  Well, they're certainly adorable, but one of the major reasons why we chose yellow-bellied marmots is because they're the longest continuously running study of mammals in the world. The data that has been collected for over sixty 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.

• 5:03Ira Flatow?

  And let's, speaking of stress, tell us what kind of stressors they go through in the wild.

• 5:08Speaker 05

  Yeah, so the 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 out mother? Or did your mother not have a lot of mass going into the pregnancy? And even losing your mother can have important consequences.

• 5:51Ira Flatow?

  And they have to deal with us humans too, right?

• 5:53Speaker 05

  Absolutely.

• 5:55Ira Flatow?

  Yeah, were there any results that were surprising to you?

• 5:59Speaker 05

  Overall, we were hoping that we would find this decrease in survival probability with increasing adversity, uh, 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 experiencing multiple ones of them, did. So that's the main thing.

• 6:30Ira Flatow?

  Yeah, so, so how now that you have this index, this cumulative adversity index, how do you use it?

• 6:38Speaker 05

  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 a 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.

• 7:06Ira Flatow?

  Yeah, it sounds like it could help local governments focus on specific strategies to protect these populations, especially all the stressors that people give them, light, sound, pollution, stuff like that.

• 7:19Speaker 05

  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 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,

• 8:04Speaker 05

  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.

• 8:30Speaker 05

  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 hard or impossible to do.

• 9:00Ira Flatow?

  Well, good luck to you. I want to thank you for taking time to be with us today.

• 9:04Speaker 05

  Thank you so much.

• 9:06Ira Flatow?

  So she'll Ortiz Ross, a doctoral student in ecology and evolutionary biology at UCLA.

• 9:15Speaker 03

  After the break, we'll talk to one scientist who thinks CAR T cell therapy could be a silver bullet for autoimmune disease.

• 9:27Speaker 01

  WNYC is supported by Bayer. Every day in America, science delivers, not just in the headlines, but in the moments that matter most. Science is a journey, one of curiosity, persistence, and progress. It's about asking questions, testing, learning, and improving again and again. Science delivers harvests that feed families, tools that help farmers grow more with less, and new ways to protect land for generations to come. Let's keep asking, keep testing, keep discovering, so science can keep delivering. Learn more at science delivers dot com.

• 10:02Speaker 06

  I'm Kevin Roos. And I'm Casey Newton. And together, we've been tech journalists for decades. Now, we're your hosts of Machine Gods, a new podcast from NPR that makes sense of what AI means for your work, your life, and all of our futures. Twice a week, we'll be exploring the biggest moves in tech and give you unmatched access to the real titans of industry. Listen to Machine Gods from NPR on the NPR app or wherever you get your podcasts.

• 10:30Ira Flatow?

  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 CAR T-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?

• 11:11Ira Flatow?

  Joining me is Daniel Baker, immunology PhD 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.

• 11:23Speaker 04

  Thanks, Ira. It's great to be here.

• 11:25Ira Flatow?

  All right, let's do the ABCs, Daniel. Give us a brief reminder of how CAR T-cell therapy works.

• 11:32Speaker 04

  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.

• 12:12Ira Flatow?

  Wow, wow. So, it could potentially be used in all kinds of diseases?

• 12:17Speaker 04

  That's right. While CAR T-cells have shown 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?

• 12:32Ira Flatow?

  And so now we're seeing promising results treating autoimmune diseases. Tell us how that works. What diseases are we talking about?

• 12:41Speaker 04

  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 CAR T cells actually working is in these really refractory cases where patients have been on courses of treatments, some of them, you know, for decades.

• 13:01Ira Flatow?

  Right.

• 13:02Speaker 04

  And the question is, could something that is a little bit more potent than an immunosuppressive, 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, you know, 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 CAR T cell therapy.

• 13:40Ira Flatow?

  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 CAR T cells to treat autoimmune conditions. What was your response to reading this paper?

• 13:55Speaker 04

  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, CAR T cells are extremely powerful. And it's, you know, it's really a new paradigm in medicine, using a patient's own cells to target disease. But one of the difficulties that we have to face as a community is if CAR T 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, you know, 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

• 14:38Speaker 04

  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 the most exciting part of the the study from China was, you know, in three patients, they took donor cells from a healthy donor, they made CAR T cells, CD19 CAR T 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,

• 15:20Speaker 04

  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.

• 15:28Ira Flatow?

  And did they see it work in those three patients?

• 15:31Speaker 04

  Exactly. What was so promising about this is they saw in all three patients, the CAR T cells in grafts. So they looked in the blood, weeks and months later, and they saw CAR T cells there. Then the most important question is, are the CAR T 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 contexts with autologous CAR T cells. And they saw improvements in all disease context. 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

• 16:15Speaker 04

  that there's any effects being seen using donor CAR T cells in order to treat autoimmune disease.

• 16:21Ira Flatow?

  So this is really, I mean, three patients, this is really early stage, right?

• 16:25Speaker 04

  Yeah, you're absolutely right.

• 16:27Ira Flatow?

  How do you scale this up to see if it would work?

• 16:30Speaker 04

  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 CAR T cells? And what does the safety look like? So I think very quickly, we will get a sense on autologous CAR T 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 allogeneic, or maybe even in vivo, CAR T cells could potentially be a therapeutic avenue for a subset of patients.

• 17:04Ira Flatow?

  You mentioned safety. Of course, we're always concerned about safety first. Are there any safety drawbacks to this treatment?

• 17:12Speaker 04

  Yeah, I think the safety concerns are the things that need to be emphasized. One of the things that we were really worried about is CAR T cells in cancers have a whole profile of safety concerns that we have to be worried about. This hyperinflammatory response because your CAR T cells are working, they're seeing tumor and they're expanding. And so when CAR T 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, phase two clinical trials to actually see what the safety and efficacy looks like. But speaking broadly, these CAR T cells in autoimmune disease look much safer than what we see in cancer.

• 17:57Speaker 04

  So most patients have less than grade three cytokine release syndrome. I know that there's been one report of 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 an autoimmune 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 huge target burden. And so your CAR T 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.

• 18:39Speaker 04

  And that's being borne out and time will tell how long that is true, but we'll see.

• 18:44Ira Flatow?

  Right. Any tests planned here for the US?

• 18:47Speaker 04

  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. 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.

• 19:06Ira Flatow?

  So what could this mean then for the future of medicine if we're able to scale donor CAR T cell treatments?

• 19:14Speaker 04

  At the 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 CAR T cells, and I think lots of us think of CAR T 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 CAR T cells and 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

• 19:56Speaker 04

  use CAR T 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 and 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.

• 20:32Ira Flatow?

  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 CAR T 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?

• 20:55Speaker 04

  Yeah.

• 20:56Ira Flatow?

  When their stockholders expect them to maximize profits, which means a cure, not a cure, but a, you know, let's have them taking drugs forever.

• 21:05Speaker 04

  Yeah. Yeah, I think I think I, you know, I understand the economic implications for some of these companies. But at the end of the day, we're trying to, I mean, they're trying to capture value too. 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, we are pretty dynamic as a society and I think we'll

• 21:47Speaker 04

  respond appropriately to the promise of a new era in medicine.

• 21:51Ira Flatow?

  Daniel, I thank you for taking time. This has been tremendously uplifting. I think at a time when we need something like that.

• 21:58Speaker 04

  Thanks, Ira. It's been great to be here.

• 22:00Ira Flatow?

  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.

• 22:14Speaker 03

  That's all the time that we have for now. A lot of folks helped make the show happen, including Sandy Roberts.

• 22:21Speaker 07

  Beth Ramey.

• 22:22Ira Flatow?

  John Dankosky.

• 22:23Flora Lichtman?

  Annie Nero.

• 22:24Speaker 03

  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-Fry producer Kathleen Davis. Take care of yourselves.