Cell therapy is a promising field that uses living cells to treat disease. And it's a powerful way to improve the immune system's ability to fight cancer. But cell therapies have other potential medical applications, such as treating autoimmune diseases, cardiac or pulmonary fibrosis, and infectious diseases. In this episode of the Science with a Twist podcast, our host Rupa Pike welcomes Dr. Wendell Lim, Professor of Cellular and Molecular Pharmacology at the University of California, San Francisco. They discuss cell therapies, why they are so powerful and promising, and the biggest challenges in the field.
⚡ Cell therapy is a promising field. Cell therapies can potentially transform medicine and treat some of the most severe diseases, like cancer. Wendell says, "That's one of the innate challenges here — how do you make something that's very controlled and specific and yet also very potent enough to really overcome the disease. And that's where we really think that cell therapies can be very powerful because cells can read different signals and then process that information almost, like I said, a little computer and then make very intelligent decisions but ones that are also still very potent in terms of killing the tumors."
⚡ There are many challenges in the cell therapy field. Even though the cell therapy field is powerful, it has its limitations. Wendell says, "There are many challenges that cell therapies face. There are many challenges we face in trying to overcome, say, solid cancers. But all of these are multifaceted problems. There isn't one solution, but they have different aspects when we think about cell therapies and make them a viable platform; not only do they have to be more effective, but also issues of how to manufacture them, make them more accessible and make them cheaper are major bottlenecks right now."
⚡ Cell therapies could potentially help treat many serious diseases. Cell therapies are not only promising for cancer treatment, but they could help fight other serious diseases. Wendell explains, "I think that engineering and developing cell therapies in cancer is really just the vanguard of a bigger movement. If we really understand how living cells work and can program them in specific new ways, this could have a huge impact on a lot of diseases that we are not very good at treating. These include things like autoimmune disease or fibrosis, cardiac or pulmonary fibrosis, as well as degenerative diseases."
[00:00:00] Wendell Lim: We really think that cell therapies can be very powerful because cells can read different signals and then process that information, almost like I said, a little computer, and then make very intelligent decisions.
[00:00:13] And also ones, but ones that are still, also still very potent, in terms, terms of killing the, the tumors.
[00:00:19] Rupa Pike: Hello and welcome back to Science with a Twist, brought to you by Thermo Fisher Scientific, the world leader in serving science. I'm Rupa Pike, your host and Senior Director of Technical Affairs for Advanced Therapies at Thermo Fisher Scientific. Today, I'm excited to welcome Dr. Wendell Lim, Professor of Cellular and Molecular Pharmacology, at the University of California, San Francisco. His research is focused on basic biology of understanding cell signaling. And insights gained from cell signaling can lead to major breakthroughs in the cell therapy field, particularly the way we treat common cancers.
[00:01:37] This month is an exciting time at UCSF. On March 27th, a state-of-the-art cell therapy device development and manufacturing facility is set to open right on campus. Offering the opportunity to Dr. Wendell and many of the researchers for accelerating their work in the cell therapy space. Cell-based therapies, as we all know, play a vital role in transforming human health as they offer solutions for many unmet medical needs.
[00:02:11] So, welcome, Wendell. I am really excited to have you as our guest today. And looking forward to hearing about the exciting work that is going on in your lab. To start with, can you tell us a little bit about your lab and your research focus at UCSF?
[00:02:34] Wendell Lim: Sure. Well, thank you very much, uh, Rupa. It's really a pleasure to be here. So, my lab at UCSF is, as you said, a a basic research lab where we've been trying to understand how living cells work. And so, I think everyone understands that our bodies are made of trillions of cells. And what we have been trying to understand is how cells sense what's going around them and how they use that information and make decisions.
[00:03:02] And what's really very exciting is that over the last several years, as our understanding of how cells process information and make decisions, we've actually been able to start using that knowledge to engineer radical new platforms for therapies that is actually engineering living cells that we can program now to actually detect disease and attack it. Difficult diseases, such as cancer.
[00:03:25] Rupa Pike: That's wonderful. Very exciting. For our non-technical audience, can you briefly describe cell therapy and how it works and in case of CAR T-cell therapy, which we hear about with all the success, as an example?
[00:03:44] Wendell Lim: Sure. So, I think what is really important is to first just make it clear that cell therapies are very different from any other kind of medicine that we've used in the past. Most of the medicines that we take are molecules that we inject or, uh, swallow as pills, et cetera. And they will interact with our bodies and our cells, but they are not living entities.
[00:04:06] What we're doing in cell therapies is we're taking a living cell, for example, a cell that's part of your immune system, and reprogramming it with DNA so that it now does new things. So, this is a living entity that we put back into the body, and then it actually moves around the body and can detect things and distinguish where, it reali, recognize what is a signature of disease.
[00:04:31] And then, once it gets there, it can execute fairly complicated programs that could, for example, kill a cancer cell. So, that's the, really the potential difference between a living therapy. They're like small microscopic robots, almost, that can actually execute these, these programs.
[00:04:50] And that's why we're so excited about them and their potential for these challenging diseases like cancer.
[00:04:56] Rupa Pike: Absolutely. I, I've heard you use the term microrobots or microcell robots before and, and I think that's very interesting. So, can you give a, a little more detail on how, from your perspective, cell therapy has revolutionized and will continue to do so for cancer care?
[00:05:18] Wendell Lim: Right. So the, it was really about 10 years ago in 2013, that the first patients were treated with this kind of new therapy called a, a CAR T-cell. So, what a CAR T-cell is, we take a, an immune cell from a patient, we harvest that, and then modify it, so we put a new sensor in it that can detect cancer and kill it.
[00:05:41] And the first cases were directed against blood cancers. And what was remarkable is that 10 years ago, the first patients were given this therapy and no one really thought it would work, but it worked amazingly well for these, these particular blood cancers. And now, 10 years later, some of those first patients are still alive and still doing well.
[00:06:03] So, it really has been a revolutionary development. What we're trying to do now, a lot of focus is to make these therapies easier and cheaper, but also to really start trying to apply them to things like solid cancers, which are very difficult. So, we, solid cancers are the majority of cancers, uh, out there, but they are extremely difficult to treat.
[00:06:28] Not only there's several different issues, one is that, a drug has to be able to distinguish cancers from your own normal tissues. And, of course, that's very difficult because cancers arise from our own cells. So, they look, from a molecular standpoint, very similar to our normal cells. And that's why chemotherapies in general are, are very toxic.
[00:06:47] At the same time the, uh, therapy has to be potent enough and strong enough that it can overcome the, a lot of tumors are, what we call, they suppress the immune system. They're able to evade the immune system. And so, we need to have, uh, the therapies be strong enough to overcome those sorts of defenses of the tumor.
[00:07:06] And so, that's, one of the innate challenges here is, "How do you make something that's very controlled and specific and precise, yet also very potent enough to really overcome the disease?" And that's where we really think that cell therapies can be very, um, powerful because cells can read different signals and then process that information, almost like I said, a little computer, and then make very intelligent decisions. And also ones, but ones that are still, also still very potent, in terms, terms of killing the, the tumors.
[00:07:38] Rupa Pike: Thank you for that. That was, that was very good and comprehensive. Appreciate that. I'm really interested in a recent breakthrough from your lab that was published this last December in Science. Your lab eliminated melanoma and pancreatic cancer in mice, very, very aggressive cancers, by engineering T cells. We would appreciate it if you can share with us why this is a significant finding.
[00:08:06] Wendell Lim: Yeah. This is very important because of, you know, what I mentioned before is that a lot of cancers actually survive and grow because they are able to suppress the immune system. And that's why our own immune responses are not able to clear those. And even if we give someone, say, a CAR T therapy, you know, this cutting-edge therapy, uh, normally, these actually are not able to survive and to, and kill these, these very difficult, immunosuppressive cancers.
[00:08:36] So, what we wanted to do was to ask, "How can we support those cells and allow them to infiltrate these tumors?" And there are certain agents, uh, certain molecules that cells can make that help them survive longer and, and mount a larger immune response. And one of these are, these are so-called cytokines.
[00:08:55] One of the problems with those is that if you give them, if you inject them into a patient, they can help fi, that your immune system fight cancer. But they also have many other effects that are very toxic and really not tolerable in, in the patient, in the rest of the body. And so, what we were able to do is we were able to design CAR T-cells that when they get to the tumor only then do they start making these, this, this sort of
[00:09:18] turbocharging molecule themselves. And that actually allowed them now to infiltrate and clear these very difficult cancers like pancreatic cancer. And so, I think it really shows the kind of much more sophisticated, uh, therapeutic programs that you can have, uh, cells execute, in terms of going to very specific places in the body and executing very specific tasks.
[00:09:43] And so, you know, another example of, of something that we've been doing is here, at UCSF, as we've been dev, my lab has been developing tools to engineer smarter cell therapies. You know, we interact with a lot of great physicians working on very challenging diseases. One of them is a colleague, Hideho Okada, who is a world leader in treating glioblastoma, which is a very difficult brain cancer.
[00:10:06] Uh, almost no ways to treat that. And so, we've gotten together over the last several years, and, for example, we've been able to now design a CAR T-cell therapy that senses when it's in the brain. So, these cells now go to the brain, and only when they get to the brain do they actually start executing tasks that allow them to kill the cancer.
[00:10:26] So, this has worked very well in mice, and now we're moving it to clinical trials. And this is one of the first therapies that we're gonna be manufacturing at this new facility.
[00:10:36] Rupa Pike: That is, that is very exciting, and really appreciate the point that you made is, you know, earlier about biologics, traditional chemotherapy drugs versus cell therapy. I think the engineer, the ability to engineer the cells and to have the precision and the targeted approach, I think is going to be much better.
[00:10:58] And definitely very excited to see how things transition from the amazing research you have done then into champion manufacturing and delivering the product to the patients. I'd like to switch gears a little bit. You've built your career as a cell biologist, uh, during what has been a very exciting and transformative time, continue to make contributions to this field of cell therapy and immunotherapy.
[00:11:28] How did you initially get into the field and also, you know, can you share a little bit about your journey and your personal connection with Carl June, with, who everybody knows at this point, he's one of the pioneers in the cell therapy field?
[00:11:46] Wendell Lim: Yeah. Well, so, uh, as I said before, you know, my, my, uh, career has been focused on really trying to understand cells and how they are wired to do the amazing things that they do. Um, and, you know, this was driven largely out of curiosity, but it was probably about 10 years ago that, um, you know, I first met Carl June, and this is before there were, more than 10 years, probably 15 years ago, uh, before there were any major successes with,
[00:12:14] um, CAR Ts, therapeutically. But, uh, I learned that they were trying to do these, these remarkable things of trying to rewire the immune system in order to attack cancer, HIV, et cetera. And I realized that the, the, some of the tools and approaches that we were developing in, in thinking about how cells were wired really would plug into this and really could, could work together
[00:12:39] with cell therapies as an amazing way to bring together this idea of understanding how cells are wired and, and cell therapies. And so, for the last, really, 10 years or so, we have been, uh, very focused on bringing these ideas to immune cells and immune therapies. And I think that, that, you know, there is, you know, I think we've now shown great potential for how,
[00:13:05] you know, really, what cells can do if you program in the right way. And what is maybe the, the big challenge right now is there's a big bottleneck in making these therapies, doing the initial clinical trials with these next-generation therapies. And so, that's why, you know, being able to much more rapidly manufacture these cell therapies to test them in smaller clinical trials. These are the, the critical steps in really moving these cell therapies to the next level.
[00:13:38] Rupa Pike: Thank you. So, Wendell, as a scientist, what motivates you in your work in the field and then, you know, just in that terms of progress, in terms of advancements, what do you hope we see over the next five to ten years, in this space?
[00:13:59] Wendell Lim: Well, I think this is a really great example of where we are both learning more about ourselves and our bodies and how they work. And, at the same time, that is really enabling, you know, revolutionary new medical advances. I think, you know, we, in the research community, you know, we, we have very long timelines of trying to build up knowledge
[00:14:24] and, and the horizon for applying it is often unclear. I think that, um, you know what's really, uh, amazing about cell therapy is it, it takes knowledge that's really been built up and understanding how living systems work at the molecular scale, over the last many decades. And really integrates them in a way where we, we have a very clear, almost moonshot, like, challenge of how we actually put these, these ideas to work within the cell therapy.
[00:14:51] So, I think it's a very exciting and fulfilling time from both the scientific standpoint as well as obvious, obviously, medical and industrial perspective.
[00:14:59] Rupa Pike: Most definitely. And, uh, for all of us who've been in science and, and, you know, started at the discovery level, we all know that it's not easy. There's always challenges. So, what are some of the challenges you're currently facing? And, you know, what do you think about them, in terms of as you move forward?
[00:15:24] Wendell Lim: Well, I think that there, there are many challenges that cell therapies face. There are many challenges we face in trying to overcome, say, solid cancers. I mean, but all of these are multifaceted problems. There isn't one solution, but they have different aspects. When we think about cell therapies and make them a viable platform,
[00:15:44] you know, not only do they have to be more effective and safe, but issues of how to manufacture them, make them more accessible, make them cheaper are major bottlenecks right now. By the same token, you know, when we think about treating a disease like pancreatic cancer or brain cancers like glioblastoma, you know, we have to both, as I said, achieve very specific recognition, very precise control, but then we also have to have
[00:16:11] therapeutic actions that are strong enough that they can wipe out the, the tumor, including residual, surviving cells. So, there's not one solution for these. It really is about kind of aggregating advances in different areas so that, that ability, ability to integrate things, bring them together, and then to have more shots on goal, that's really, uh, I think what is critical in, in the next, uh, few years.
[00:16:36] Rupa Pike: Well said, Wendell. And, you know, we, we hear all of these things. Yes, cancer therapies, immunotherapies, but there is also a lot going on. So, beyond cancer, what other areas of medicine do you think cell therapy would play a big role make an impact? And then, can you share anything specific that is going on in your lab?
[00:17:02] Wendell Lim: Yeah. I think that, you know, engineering and developing cell therapies in cancer is really just the, the vanguard of, of, of a bigger movement. If we really understand how living cells work and can program them in specific new ways, this could have, uh, huge impact on a lot of diseases that we are very, you know, are not very good at treating.
[00:17:26] These include things like autoimmune disease, or fibrosis, cardiac or pulmonary fibrosis, as well as degenerative diseases. The, uh, I think that, you know, we can, in theory, design cells that could, for example, detect places where there is hyper inflammation and autoimmune responses,
[00:17:46] or in the ca, or perhaps even things like, uh, organ transplants and then in, in principle design cells that could tamp down immunity in those, inflammation in those regions. I think we're also very excited about the idea that this could move more towards a bigger vision of regenerative medicine, where we can program cells to execute regenerative, uh, and repair functions in vivo, identifying where injuries are and then executing programs that help to
[00:18:13] um, regenerate or, or repair, uh, tissues or, or other defects. And so, I think it really illustrates how, this is really, uh, new kind of platform for us to interact with our bodies. And, you know, cancer's gonna be the lead, and if we can overcome some of the problems in the bottlenecks that we have now, there's gonna be a lot of different things that we, uh, should be able to do.
[00:18:36] Rupa Pike: Thank you. On that same note, as you mentioned very eloquently, you know, fundamental biology, understanding of the cellular behavior and ecosystem is very important. Can you, in your mind, make a connection between a fundamental biological discovery cell signaling many other things, and, and take it all the way to the journey of how it impacts patient, patient care?
[00:19:08] Wendell Lim: Well, yeah. I think that, that, you know, one, over the last several decades, I think we've been very focused on sequencing the genome, identifying molecules and, you know, saying, "This gene is involved in this disease." But something that kind of gets lost in the, you know, in that kind of very focused thinking is that, you know, all of biology takes place in the context of these living cells that are,
[00:19:34] you know, have lots of genes in them and move around the body and interact with one another. And so, I think it's really interesting to try to integrate all of that knowledge from the perspective of, of the cell and, and think about what, you know, if you were a cell, you know, what, what do you need to do to,
[00:19:51] what task, what capabilities do you need to be able to achieve a certain therapeutic task. And I think it really is a, is an amazing way to integrate all that we know about how biological systems and cells work. And so, I think it's a, it's a great and, you know, obviously, there's a lot of people who are very, uh, excited about this, both from an intellectual standpoint, but also from, you know, the capabilities that, that should emerge.
[00:20:16] Rupa Pike: Yeah. So, your institution, UCSF, has decided to do something that very few hospitals and medical schools across America have done. Building a manufacturing site for cell therapies right on campus. What does this resource mean for you, your research focus, your partnership with Dr. Hideho Okada? And how do you think it will impact your science?
[00:20:47] Wendell Lim: Well, I think this is tremendously exciting, and I, I really wanna thank the leadership at UCSF and Thermo Fisher for developing this, this relationship, and this facility. The, uh, as I mentioned before, the ability to make these therapies and to try them out in phase one clinical trials is the, the real bottleneck in this area.
[00:21:11] And, you know, I would say industrially, and commercially a lot of companies are interested in the very important issues of, of kind of making therapies cheaper and more, more efficient than therapies that exist. And there's little, there's less opportunity to develop, in the context of human patients, novel next-generation therapies that will open up new areas like solid cancers.
[00:21:38] And so, the ability, uh, what we really are hoping is that this will allow us to have more shots on goals to, to shorten the time between development of an idea at the bench, uh, to being able to actually, uh, deploy it and test it in patients.
[00:21:54] Thank you, Wendell, for taking the time to tell us about your amazing research and for sharing your thoughts on what may be possible with cell therapy over the next few years. It is most definitely an exciting time for us.
[00:22:10] Wendell Lim: Well, thank you very much, Rupa, for having me here.
[00:22:13] For listeners interested in learning more about Dr. Wendell Lim's research at UCSF, please visit Limlab, that's one word, limlab.ucsf.edu. I've truly enjoyed being your host today. Thank you, Dr. Lim and UCSF, for helping us usher a new era of medicine through your amazing research in the cell therapy space.
[00:22:45] We're excited to see how this new GMP cell therapy manufacturing site on campus can further accelerate and advance research in order to bring the much-needed therapies to patients. Until next time, this is Science with a Twist.