Strengthening T-Cell Therapy for Solid Tumor Cancers with Jaehyuk Choi, MD, PhD
A new study published in the journal Nature details breakthrough T-cell immunotherapy research from Northwestern Medicine. In this episode, Jaehyuk Choi, MD, PhD, senior author of the paper, explains how a gene mutation found in T-cells of patients with lymphoma could hold the key to a potent cancer-fighting immunotherapy for solid tumor cancers, which account for 90 percent of all cancers.
“We have this incredible opportunity to do science that may actually matter to people. And I'm just humbled by the ability of how technology has enabled us to come up with a crazy idea, translate it into something that could work in these preclinical models. And then there's a path forward to see if it could possibly cure patients. ”
- Jack W. Graffin Professor
- Associate Professor of Dermatology in the Division of Medical Dermatology
- Associate Professor of Biochemistry and Molecular Genetics
- Member of Northwestern University Clinical and Translational Sciences Institute
- Member of Robert H. Lurie Comprehensive Cancer Center
- As a physician-scientist, Choi’s goal is to provide the best clinical care that's known today and improve clinical care for the future. That led him to investigate the T-cells of patients with lymphoma and better understand the powerful gene mutations present in the cancer of these patients and how to re-engineer them to fight cancer.
- Choi explains the history of T-cell therapy and its success in recent decades in treating treatment-resistant blood cancers. However, he says T-cell therapy has been less successful in treating solid tumor cancers because they create defense mechanisms that impede the effectiveness of T cell therapies.
- In the effort to identify T-cell immunotherapy for solid tumor cancers, Choi teamed up in a 50/50 collaboration with UCSF to enhance T-cell therapies for solid cancer tumor treatment using mutations created by nature, present in the T-cells of people with lymphoma.
- Choi highlights the importance of having a team that included: Kole Roybal, PhD, Director of the Parker Institute for Cancer Immunotherapy at UCSF and an innovator in T cell technologies, Roybal’s student Jule Garcia, PhD, and Northwestern University post doctoral student Jay Daniels, PhD.
- Seventy of the 71 mutations studied were sanctioned by Choi, but Daniels championed the 71st gene fusion, CARD11 PIK3R3. Through a series of experiments the team discovered this fusion protein seems to be very powerful at supercharging T-cells, specifically in their ability to kill tumor cells. Daniels made the discovery on a late December day in the lab and called Choi with the news that “it actually worked, it really worked.” Choi says this was a touching moment.
- This supercharged T-cell, engineered with CARD11 PIK3R3, has been tested in about seven different human and animal models with success and Choi says that “highlights the ability to use this as an almost off- the-shelf type enhancement that can be used for many different T-cell therapies for many different cancer types.”
- There may be some with a safety concern over this therapy, because it is based on a cancer mutation, some worry that the potential therapy could cause cancer. Choi says the team is engineering mechanisms to regulate gene expression and ensure safety.
- The next step is to test in human clinical trials, which Choi envisions could first be used as a last line of defense in cancer patients who have exhausted all other treatments. Such trials would take place at academic medical centers like Northwestern Medicine.
- Choi and Roybal founded a company called Moonlight Bio to take the genetic engineering principles they’ve discovered and apply them to FDA approved therapies that can be given to cancer patients. Both Daniels and Garcia have joined the company, and the team hopes to have their therapy in clinical trials in the next few years.
Recorded on February 5, 2024.
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Choi has affiliations with and financial interests in Moonlight Bio. Northwestern University has financial interests (equity, royalties) in Moonlight Bio.
Read the Full Transcript
[00:00:00] Erin Spain, MS: This is Breakthroughs, a podcast from Northwestern University Feinberg School of Medicine. I'm Erin Spain, host of the show. Gene mutations that make cancer cells so powerful and tough to defeat are now being used by Northwestern Medicine scientists to strengthen immune cells and wipe out lung and stomach cancer tumors in mice. Plans are already underway to advance this next generation T cell immunotherapy treatment concept in human clinical trials and could have a tremendous impact on the care and survival of people with any type of solid tumor cancer, which accounts for 90 percent of all cancer diagnoses. Dr. Jae Choi, Associate Professor of Dermatology and Biochemistry and Molecular Genetics at Northwestern University Feinberg School of Medicine, is the co author of a recent study published in the journal Nature that details this breakthrough research that he and his team conducted along with colleagues at the University of California, San Francisco. He joins me today with the details. Thank you so much for being on the show.
[00:01:17] Jaehyuk Choi, MD, PhD: Thank you so much for having me.
[00:01:18] Erin Spain, MS: You are a physician scientist here at Northwestern medicine. So you are not only treating patients with diseases, such as T-cell lymphomas, but you're also studying them in your lab. Tell me about your work and how these two worlds work together.
[00:01:32] Jaehyuk Choi, MD, PhD: So I see patients predominantly with these unusual T cell cancers and T cell lymphomas. And I've just been struck as a physician to ask why do patients have such unusual presentations? What makes one patient different from one another? And what are the best ways that we can possibly cure these patients? And so it's really been an inspiration for our lab to think about. This is what the textbook says, but it doesn't really cover or explain what happens to most patients. Can we identify questions we can ask scientifically that would distinguish one patient from another? And so the goal as a physician is to provide the best clinical care that's known today. And our goal in the lab is to improve clinical care for the future.
[00:02:12] Erin Spain, MS: One of the therapies that has really changed the way that you're able to treat these patients is T cell therapy, immunotherapy. Just give us a little history lesson, a little background on this type of therapy, how it's used in your patients with lymphoma.
[00:02:25] Jaehyuk Choi, MD, PhD: We can take T cells from a patient, engineer them with synthetic receptors to identify and kill the cancer cells in the patients. And it seems to have this amazing effect on treatment resistant blood cancers. And it's been able to provide amazing responses in people with B cell leukemia and many patients with B cell lymphoma. It doesn't work for everybody, but for the people it works for, it really seems to provide long lived, durable cures. I think that actually the first patient was a pediatric patient when treated and she was cured and now just enrolled in college at UPenn.
[00:02:56] Erin Spain, MS: Incredible. So this T-cell treatment, this idea of using T cells, your own immune system to fight cancer is something that a lot of scientists want to push into solid tumor cancer treatments, breast cancer, lung cancer, stomach cancer. But it hasn't been successful and treating these cancers. Why is that?
[00:03:16] Jaehyuk Choi, MD, PhD: So it turns out solid tumors which make up 90 percent of cancers, create their own little defense mechanisms, fortress, or all these different things that are really designed to thwart the immune system. And so it probably is required evolutionarily to actually prevent them from being detected and treated in the first place, and that's why patients develop these tumors. But those same defenses are really strong and prevent These engineered T cell therapies from being able to access and kill these tumors.
[00:03:43] Erin Spain, MS: This is an issue that a lot of people are trying to tackle and understand. And in the paper that we're talking about today, you really did have a breakthrough. Tell me a little bit about the team that was assembled to discover this breakthrough, and then walk me through what was found.
[00:04:00] Jaehyuk Choi, MD, PhD: It really was a 50-50 type collaboration done with my friend and colleague Kole Roybal at UCSF. He's truly an innovator in T cell technologies and has been really a powerful mover in CAR T development. The first authors are Julie Garcia from UCSF , Jay Daniels from Northwestern, Kole Roybal, who's at UCSF and myself. Two things that are really interesting and really important here is that, number one, if I were trying to improve T cell therapies at the lab, I would make a guess, show that it works in some kind of tissue culture dish, then I would show it works in mice, and then hope it works in people. In this particular case, we learn from things that happen in people, have been validated in people, and then just study the mechanisms in the dish and in the mice, and therefore think it's a clear path to getting into people. The second thing, which is really important, is that we've learned so much science and have incredible technologies based on CRISPR and these different ways to edit the genome. But actually, nature has even a broader, deeper toolbox. They can use any mechanism to make these kinds of modifications. So, while we can easily modulate gene expression up and down with CRISPR, nature has found out that you can create these point mutations and create these gene fusions that have outsized effects on T cell biology.
[00:0:43] Erin Spain, MS: So, as you mentioned, you're using T cells from patients with lymphoma and your lab. And you and Jay Daniels, your MD-PhD student were actually able to identify a suite of 71 genes associated with this malignancy. And there was a specific fusion mutation of two genes that is really powerful. And that is detailed in the Nature paper. Tell me more about that.
[00:00:00] Jaehyuk Choi, MD, PhD: Jay and I were actually mostly lymphoma biologists. And this was our first foray into adoptive cell therapies. And so this is one of the reasons why it was really critical to partner with our colleagues at UCSF who have much more expertise in this area. I actually sanctioned 70 of the 71 mutations we studied. But my student, Jay Daniels, he's the one who really championed the 71st gene fusion, CARD11 PIK3R3. So what we normally do is we look for mutations that occur more often than expected by chance because we infer that they create this huge fitness advantage which allows them to be seen in multiple people. But Jay found this one paper where this one fusion gene was detected and he was absolutely certain that it must have a huge effect on T cells and insisted that it be part of the suite of genes that we test. And so in this case, what the fusion does, it actually takes one gene, CART11, that plays an important role in T cell biology, gets rid of some of the inhibitory domains, or the breaks that prevent it from being optimally or maximally activated, and then combines it with a protein binding domain from another gene called PIK3R3. Now, we don't understand the full biology, but this fusion protein seems to be very powerful at supercharging T cells, specifically in their ability to kill tumor cells. And I remember actually getting a call from my student, right before he's about to go home for Christmas. We had this really touching moment where he just said, it actually worked, it really worked. And we were able to find that this fusion actually increased T cell potency over 99 percent. Over hundreds to ten thousand fold more than the other methods being used, and so it was really a touching moment.
[00:07:19] Erin Spain, MS: Such a fantastic story of the role that a trainee can play and pushing forward big discoveries. Another interesting part of this research is that you're really using nature as a roadmap. Tell me about that.
[00:07:34] Jaehyuk Choi, MD, PhD: What's really been compelling about this discovery is that actually it really just makes sense. I think a lot of people really believe that we're not smart enough to make the best improvements to these T cells. And learning the lesson from, like, nature's road map is actually a really clever acknowledgment of our humility that we just don't know what is actually the way to improve T cell therapies in patients. And so, I think there's been a lot of enthusiasm with the concept of utilizing nature's roadmap to be able to give T cells a superpower. But what's really been extraordinary that people have really loved is that it seems to work in almost every situation. So we've done this on human T cells against human cancers, we've done this on mouse T cells against mouse cancers, we've done this against blood cancers, solid tumors, we've done this with an intact immune system, we've done this without an intact immune system. So I think all in total, there are about six or seven models in which it's worked, which really highlights the ability to use this as an almost off the shelf type enhancement that can be used for many different T cell therapies for many different cancer types.
[00:08:44] Erin Spain, MS: Are there safety concerns or potential challenges here about incorporating these mutations into future T cell therapies?
[00:08:51] Jaehyuk Choi, MD, PhD: So the first thing that we'll say is it turns out that these mutations we really focus on them because we thought we can achieve this Goldilocks-like effect. We wanted them to make T cells stronger, but we wanted them still to be stronger specifically in the context of being able to identify and kill cancer cells. So if it made them so strong that they were able to be Inflammatory without cancer cells being present, that would not be something we would be desirable for our engineering purposes. So one of the reasons why this approach is so useful is it turns out many of these mutations in these T cell lymphomas actually require what we call antigens to be able to activate their true potential to supercharge T cells. And in this case, what that means is if the T cell has a receptor that recognizes something on the tumor cell, it's intrinsically designed to be able to supercharge in that situation. However, if the T cell is not in the presence of a cancer cell, it's designed to be able to disappear. Because this mutation comes from lymphoma and is brought into T cells, there'd be many people who are rightly concerned that this could cause cancer. We don't think that's going to be likely, but just in case, we did these experiments which were incredibly long and tedious, but we have kept the cells in animals for over a year, which is almost the equivalent of human 30 to 40 years and we have not found that they cause cancer and in fact we found that most of them seem to disappear entirely from the blood in the absence of cancer and so what we think is that this is a possibility that this could show that this mutation can be safely introduced to T cells to fight cancer. I will also say that one of the reasons we hooked up with our colleagues at UCSF is that they were very elite in being able to think about regulating expression of different genes in T cells. So they designed these different circuits that would enable them to be only expressed in specific situations and in specific environments. And so I think that even if we believe this is safe, we can still engineer additional safety mechanisms, including killing switches to kill the T cells, as well as regulatory circuits so they're only expressed in the tumor microenvironment. Our goal is still always to just have the T cells reveal their superpower in the setting of a tumor, the example I like to give is we hope the T cells are like Clark Kent in a normal setting and that they're Superman only in the face of cancer, and when the cancer is cured, they go back to being Clark Kent.
[00:11:27] Erin Spain, MS: At what stage in treatment do you envision a T cell immunotherapy like this to be given?
[00:11:33] Jaehyuk Choi, MD, PhD: It's a great question. So I think right now it'll probably be used in patients who failed other treatments, kind of like a last line of defense, but that's the way most clinical trials go. You try to use it for people who fail other therapies. But the amazing opportunity and promise that immunotherapies provide is that you have an opportunity to cure patients with possible minimal side effects because the immune system is designed to be highly specific and really only be able to clear bacteria, viruses, etc. And we want to take advantage of that specificity to try to cure cancer. So there's many different potential advantages of the system that could eventually make it first line. The second thing is that the unique aspect of these T cell therapies are that they are what we call living drugs. And so instead of being a drug you take by mouth or by through the veins, like every day, every month, or even once a year, these cells are designed to be given once. They're designed to be activated when you have the tumor cells, Go away when the tumor cells go away. But a small percentage, we're hoping will cause long lived memory that enables your immune system to always be able to recognize and kill the cancer cells if they ever recur.
[00:12:44] Erin Spain, MS: So for now the thought is that someone with cancer would be given this therapy during surgery, after surgery, in lieu of surgery.
[00:12:51] Jaehyuk Choi, MD, PhD: There's a possibility this will be given for a lot of patients who get surgery or not surgery, but I think that the real unmet need right now are people who are not eligible for surgery, for whom the cancer has spread from the original site and is disseminated through their body and they really aren't a good surgical candidate. So what we are hoping is that we can provide options for those patients, who are not eligible for surgery. So we're hoping to replace chemotherapy and other drugs with this T cell therapy.
[00:13:19] Erin Spain, MS: Right away, I think of something like pancreatic cancer and how a lot of times it has spread and there is no option for surgery. So those are the types of patients that you could see being enrolled in a clinical trial.
[00:13:30] Jaehyuk Choi, MD, PhD: That's right. So, we still have a little bit of work to do to actually bring it to patients, but, I will say in another personal note, my mother in law passed away from pancreatic cancer, and that's not anything that we study in the lab until now. But actually, we think this is a possibility that we can do something that could potentially cure patients like her in the future.
[00:13:47] Erin Spain, MS: So we hope to be talking to you in the future about clinical trials using these T cell therapies at academic medical centers, like Northwestern Medicine and UCSF, but in the meantime, you and your colleagues who worked on this paper, have developed a company called Moonlight Bio. Tell me about the company and the role that it's going to play.
[00:14:07] Jaehyuk Choi, MD, PhD: So one of the advantages of partnering with Kole Roybal and others at UCSF is that they have the pipeline and the ability to engineer these cells and actually generate an academic clinical trial. They have a ton of experience with this. But Eventually, to be able to offer this therapy at scale, to de-risk it, to provide all the side effects and all the mitigating engineering you'll need, this has to be done in industry. And so to really spur this along, Kole Roybal and I co founded a company called Moonlight Bio. It's in Seattle, Washington. And its sole purpose is to take these genetic engineering principles and be able to apply them to FDA approved therapies that can be given to any patient around the country, if not the world.
[00:14:52] Erin Spain, MS: Describe to me the reaction from the community, from your fellow researchers around the country or world who have heard about this discovery. What's the reaction been like?
[00:15:02] Jaehyuk Choi, MD, PhD: I think in general people love the story, so there's a personal component, I think the ability that Kole and I and Jay and Julie, our trainees, were able to collaborate on something like this is just a really remarkable example of how science is a team sport and people love to hear about people are being cooperative and really joining forces to utilize their expertise to really make powerful discoveries. But I think that what's been really remarkable, it's just the power by which these seem to work. When we did the study that I described with my student Jay, we actually powered it with so few cells, only 20, 000 cells, which is a tiny amount. And in people you give usually millions, hundreds of millions, maybe even billion cells. And then we were doing this condition called non lympho depleted. So in humans who receive T cell therapies, they have to receive chemotherapy before they receive the T cell therapy in order to make space for the new T cells to arrive and fit in. We didn't have to do any of that. And still the 20, 000 cells provide durable cures for our Mice in our preclinical models. So the reason why people, I think, are also really excited is just the potency that we're able to achieve and being able to do this in such a safe but effective way for many different cancer types is just something that's really resonated with the community. And I think there's some people who think that we may have potentially solved this problem of persistence that is the main problem for why T cells don't survive in solid tumors. What we've basically found is that T cells in the solid tumors will not survive what we call persist, much less thrive, unless they acquire abilities that T cells normally don't have. And we think that our modification, this CART11 and PIK3R3 fusion, is one possibility, if not the best possibility, to make it thrive in that microenvironment.
[00:16:48] Erin Spain, MS: What's your expectation and what's going to happen with this newfound knowledge?
[00:16:52] Jaehyuk Choi, MD, PhD: I think there's going to be a lot of interest in both here at Northwestern, UCSF and around the world about our discoveries. People are going to try to pick it apart, understand why it works, how it works, and whether this can be improved upon in the future. And I think this is the great part about science. You know, we live in a world where we try to report our findings and move the field forward. And many people are interested about the biological, molecular, biochemical, and immunological implications or findings. I think the goal for all of us is to really try to find new therapies for cancer. We think Moonlight Bio has a really good shot at being able to do so, but if this leads to discoveries by others that really sort of promotes the process, I would be more than happy.
[00:17:30] Erin Spain, MS: When could we see clinical trials taking place?
[00:17:33] Jaehyuk Choi, MD, PhD: We think that actually it could occur within one to two years that we could try to actually get in front of the FDA. But it moves fast. I think one of the things that just want to highlight again is that the technology is there, but also we have amazing people who are associated. Kole is a very talented investigator who has been really adept at thinking about how to bring his technologies into the clinic. Jay and Julie, the lead authors, have both gone into Moonlight Bio, which is just a tremendous opportunity for them to expand upon their original discoveries. And we have an amazing team that's really sort of pushed this forward. So, I think the technology enables it, but the team itself has really been outstanding at being able to push this through.
[00:18:12] Erin Spain, MS: What message would you like to leave us with today about the significance of this finding?
[00:18:16] Jaehyuk Choi, MD, PhD: We have this incredible opportunity to do science that may actually matter to people. And I'm just humbled by the ability of how technology has enabled us to come up with a crazy idea, translate it into something that could work in these preclinical models. And then there's a path forward to see if it could possibly cure patients. And there's so many parts of this, the collaborations, the power of teams, the power of this amazing group of students and trainees we have at Northwestern. But the thing that it always makes me think about is why we as scientists, physicians, and physician scientists should be optimistic about the future. I think biology can't be stopped. Through innovation, we'll be able to solve many of the problems facing us today.
[00:19:00] Erin Spain, MS: That's a fantastic note to leave us with today. Thank you so much for your time, Dr. Jae Choi.
[00:19:06] Jaehyuk Choi, MD, PhD: Great, thank you, Erin.
[00:19:07] Erin Spain, MS: You can listen to shows from the Northwestern Medicine Podcast Network to hear more about the latest developments in medical research, health care, and medical education. Leaders from across specialties speak to topics ranging from basic science to global health to simulation education. Learn more at feinberg. northwestern. edu slash podcasts.