The future of immunotherapy
Biochemist Lingyin Li survived breast cancer at just 30 and now works to harness the human immune system to fight cancers that have long evaded treatment.
T cells, she says, are powerful cancer killers, but they can be oblivious. She and her lab colleagues have discovered a masking enzyme that squelches the immune system’s “danger signals” and are now developing drugs to block that enzyme. She likens her work to an arms race between cancer and immunotherapy. “The cancers are not getting smarter, but we are,” Li tells host Russ Altman on this episode of Stanford Engineering’s The Future of Everything podcast.
Transcript
[00:00:00] Russ Altman: This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. I thought it would be good to revisit the original intent of this show. In 2017, when we started, we wanted to create a forum to dive into and discuss the motivations and the research that my colleagues do across the campus in science, technology, engineering, medicine, and other topics. Stanford University and all universities, for the most part, have a long history of doing important work that impacts the world, and it's a joy to share with you how this work is motivated by humans who are working hard to create a better future for everybody. In that spirit, I hope you will walk away from every episode with a deeper understanding of the work that's in progress here and that you'll share it with your friends, family, neighbors, coworkers as well.
[00:00:48] Lingyin Li: It is an arms race between cancer and our arsenal of immunotherapy, so we have to outsmart cancer. Cancers are not getting smarter. We are, and we have figured out a way to blow cancer's covers. We're on the right track and we're going to win this race.
[00:01:09] Russ Altman: This is Stanford Engineering's The Future of Everything, and I'm your host, Russ Altman. If you're enjoying the show or if it's helped you in any way, not a very high bar, any way, please consider sharing it with friends, neighbors, relatives, colleagues. Word of mouth is a great way to spread news about the podcast and therefore about The Future of Everything. Today, Lingyin Li will tell us that the immune system wants to fight cancer with us, but the cancer sometimes evades the immune system by camouflaging itself. She and others have found ways to remove that camouflage so that we can use our immune system to fight cancer. It's the future of immunotherapy. Today, we're gonna continue our new feature called the Future In a Minute, at the end of our discussion, I'm gonna ask Lingyin Li some few rapid-fire questions, and I'm gonna ask her for some rapid-fire answers. It'll be a summary of The Future of Everything. Before we get started, a reminder to please tell your friends, neighbors, colleagues, relatives, anybody you know, and like about The Future of Everything to spread the word about the podcast.
[00:02:14] So the immune system is a very powerful system. We know that it helps us fight bacterial and viral infections, but only in the last few years have we fully appreciated that cancers can also be a target of the immune system. There's been a whole new field of immunotherapy that has been incredibly revolutionary for cancers in the blood. And the reason it works in the blood is because immune cells are circulating in the blood, and if the cancer cells are right next to them, they can attack those cells and kill them with a little bit of help from some new age medications. But solid tumors, things like breast cancer, brain cancer, pancreatic cancer, they don't have as many immune cells within them, and therefore, immune therapy or immunotherapy hasn't been as successful. Well, there are new opportunities now because scientists have figured out that these solid cancers are camouflaging themselves to remove any signal or any sign that they're in the area. Now, scientists have figured out ways to uncover that camouflage and make the cancer more obvious to the immune system, which then can attack and kill it. Well, Lingyin Li is a professor of biochemistry at Stanford University and an expert on immunotherapy, biochemical signaling in cancer, and how to use those two together to create new treatments for solid tumors that need help from the immune system.
[00:03:38] Lingyin, thanks very much for joining us today. And how did you decide to focus your work on the immune system and how it can help with cancer?
[00:03:47] Lingyin Li: That's, that's a great question. I was a chemist by training. Chemists have tools. We don't exactly have problems. We look for problems with our tools. Um, so I went to Harvard Medical School for my postdoctoral research looking for problems. And the problem was presented right in front of me. When I turned 30, I was diagnosed with breast cancer. Um, that's when I had to study the history of cancer treatment, what works, what doesn't work. And I learned that immunotherapy just became online. It started to cure patients with late-stage melanoma cancer. However, it does not work for breast cancer patients. So that's when I started, uh, to focus my research on how to make immunotherapy work for solid tumors such as breast cancers.
[00:04:31] Russ Altman: So yeah. You mentioned solid tumors and I know that in your writing and your speaking, you talk about how a lot of this immunotherapy, and we have to get back to that 'cause it's a complicated idea, but since, since we started, a lot of these immunotherapies, their initial success was on, um, bloodborne cancers that aren't solid, they're like circulating in the blood and the immunotherapy seems to work better there. Although you did mention melanoma, so it sounds like there's a special opportunity for solid tumors that makes them different.
[00:04:58] Lingyin Li: Yeah, that's exactly right. So, uh, we have to understand what is actually the workforce for, uh, immunotherapy is actually T-cell, killer T-cells. So, these cells engage into one-on-one combat, okay? It literally grabs onto cancer cells and inject its toxin into the cancer cells. So, in order for this to work, that T-cells must directly contact a cancer cell. So, this is particularly easy when you have circulating tumors 'cause T-cells are in circulation, in solid tumors t-cells are not there. Nobody told them there are cancers. Why would T-cells be there? So that why we work on, um, to, uh, bring the T-cells into solid tumors.
[00:05:38] Russ Altman: Okay. So, I, I was gonna say that in order to really appreciate immunotherapy, we're gonna need you to give us a little tutorial on the immune system. And you actually just did that. So that an important component of the immune system are these T-cells that can kill cancer if they're in the right place. Um, uh, and then on cancer, is there anything we need to know about cancer and its special features to appreciate how this immunotherapy might work? I think a lot of people might be surprised. They think of the immune system as something that is for bacterial infections or viral infections. They not, might not think of the immune system as being involved with cancer. And so maybe you can just tell us how that connection gets made.
[00:06:15] Lingyin Li: Yeah, that's, that's a great question. So, as it turns out, um, our first line of defense, even for bacteria, for viruses, is not T-cell. So, they're called our adaptive immunity. Um, so typically during bacterial infection are innate immune cells. They have to recognize these, uh, threats within seconds, okay? So how they recognize these threats is through pattern recognition, just like AI, okay? So, bacteria don't look like our cells, um, right? Neither do cancer cells. So, um, uh, for example,
[00:06:50] Russ Altman: Even though they're derived from our own tissues, they don't look quite right.
[00:06:54] Lingyin Li: That's right. Because they have mutations, okay? So, cancers typically have accumulated about six mutations in order to become cancerous. And those mutated peptides, when they go onto the surface of a cell, they don't look quite right, okay? So, then these innate immune cells would put this, uh, uh, these bits and pieces of muted peptides on themselves, um, and then go onto the lymph nodes to go tell T-cells, this is what cancers look like, okay? They have this specific mutation. Go and kill that specific cell with this specific mutation.
[00:07:28] Russ Altman: Okay. And, and that works well for the bloodborne ones. But as you were saying, these, these special T-cells, which are kind of our friends, they're trying to do the right thing. They're not active. And I know this gets us into your research. So, tell us what are the opportunities to, to tell those T-cells, you need to go fight the solid tumors like breast cancer, just like you are for leukemia and lymphoma and these other ones.
[00:07:51] Lingyin Li: Yeah, this is, um, you know, uh, the, the opportunity right now is to basically awaken our innate immune cells to tell them to start picking up these tumor associated antigens, it's a big word, but really it's just these muted peptides, to pick them up, put 'em on yourself, just like a decoration, okay? And then go inform, become a informant. So, this is the most important step. Um, so to do that, we first have to understand, uh, how these innate new cells are even activated. Um, yeah. So, if you could allow me, um, immunotherapy, you know, you ought to talk about, um, the future of immunotherapy. We kind of have to learn a little bit about a history of immunotherapy.
[00:08:33] Russ Altman: Perfect. Let's do it. Let's do it.
[00:08:35] Lingyin Li: Great. Yeah. So, um, you know, a hundred years ago a doctor named William Coley was already experimenting with immunotherapy. Um, so he had this observation that a patient with sarcoma got a nasty infection infected with, um, this, uh, streptococcus pyogenes, uh, bacteria in its, uh, bone cancer and after its immune system warded off the infection itself, the cancer itself also disappeared. So, then he started treating patients with isolated bacteria. First was live, and later he killed the bacteria before he inject them into patients, uh, to awaken their immune system with mixed, uh, results, okay? So now a hundred years later, we actually understand, um, uh, the, the mechanism of that. Uh, basically, uh, bacteria don't look like our cells, right? So, he was injecting these bacteria patterns into the patient and say, hey, wake up. Okay, don't sleep at wheel. Uh, so, um, now our,
[00:09:36] Russ Altman: And was the infection in the sarcoma itself.
[00:09:40] Lingyin Li: Um, he wasn't injecting, uh, later the toxin into the sarcoma themselves, but the original patient, the infection was, was in the cancer. So, you touched upon a very important question, which is what he didn't do, right? He did not inject this toxin directly into cancers. Um, because you need to immunize our immune system against tumors, uh, not against something else, right? So, uh, for that we had this, uh, question, which is how do cancers, uh, naturally send out toxin without us injecting toxins into solid tumors? Um, so the, the, the molecule cancers actually send out was discovered, uh, about, uh, twelve years ago now. And, uh, this is a molecule, uh, which we, we later, we didn't discover the molecule. We understood how it works, and we later named it, uh, uh, as an immuno transmitter, okay? So now we know that, uh, when cancers have mutations, start to collect mutations, or when cancers start, keep on dividing, they get old, they cannot keep their DNA, uh, inside their nucleus where it should be, inside their mitochondria where it should be, they start to spill out this genetic material.
[00:10:54] Russ Altman: And that's abnormal. Cells normally don't do that, but the cancer is kind of outta control and it's, it's spilling DNA into its body.
[00:11:02] Lingyin Li: That's, that's exactly right. Yeah. When this DNA was detected inside the cell's body, not inside, not well packaged, then, um, we have pattern recognition, right? Our innate immune system, we recognize it, and then we make this danger signal, this immune, uh, transmitter or this toxin cancer specific toxin. So we discovered that cancer cells always make this toxin and this, uh, molecule is even more enhanced when we treat it with immune, uh, with um, uh, excuse me, not immunotherapy with, uh, radiation therapy or with chemotherapy to mess them up even more, uh, they would spit out more of this, uh, immuno transmitter. Um, so this is, uh, actually what showed this is how immuno, uh, sorry, this is how radiation therapy, uh, works, can, uh, sometimes elicit systemic immune response against the cancers, even though the beam was just focused on one tumor to begin with.
[00:12:00] Russ Altman: Yes, yes. So, so all cancers, or virtually all cancers, make this molecule that is actually a, it's like they're waving their hands saying, I'm a cancer cell. So, um, that seems to be like a good thing for those with cancer, right? Because you could use that, um, but I, I think the, the story gets more complicated.
[00:12:18] Lingyin Li: That's exactly right. Um, and, um, you know, uh, for the most part our immune system, uh, our innate immune cells do answer the call from this immuno transmitter. They go in, right? They respond when cancers emit the signal. They go in, they put a piece in the business of the cancer peptides on themselves. They go in to inform the T-cells and the T-cells, when they see a match, they say, hey, I know that peptide, that T-cell clone would multiply, multiply. This is very important because it's one-on-one combat, right? So, the T-cells would get into the tumors and um, uh, each, uh, T-cell that recognizes the cancer would grab up the cancer, inject the toxin. Um.
[00:13:01] Russ Altman: Good, good. So that sounds like that sounds like a great system.
[00:13:04] Lingyin Li: Yeah. This is a great system. It works most of the time, except when it doesn't.
[00:13:11] Russ Altman: Great. And when is that?
[00:13:15] Lingyin Li: So that's when cancers, we will say, have evaded our immune detection. And we have discovered one way and a very fundamental way of how cancers, um, uh, break this, um, uh, messaging system. Uh, they put on a mask on themselves. It's actually an enzyme that chews up the standard signal, okay?
[00:13:36] Russ Altman: Ah. So, it's as if the cancer knows, and I say know in quotes. But it can, it, this, the cancer cells, if they keep releasing this toxin, they're gonna be killed. And so, there's a huge pressure on them to come up with a way to not have this toxin be released so that they can evade these killer, these T-cells that are gonna try to kill them if they do release it. I mean, I'm, I'm just wanting to make sure I'm following. Is that so far so good?
[00:14:01] Lingyin Li: A hundred percent. Yeah.
[00:14:03] Russ Altman: Good. So, keep going. So now, but then you said, what do they do when they realize, uh-oh, I'm making this toxin and it's making me too obvious?
[00:14:10] Lingyin Li: Yeah, they, um, put on this protein, which chews up, um, this toxin, this immuno transmitter and this protein, I'm going to mention its name 'cause I'm very proud of it because I purified this protein out of a calf liver.
[00:14:26] Russ Altman: Okay. So, this is many years of your life, and we need to be able to tell people, who does this bad thing, who is helping the cancer?
[00:14:33] Lingyin Li: Yes. Name and shame. And the name of this protein is ENPP1.
[00:14:41] Russ Altman: E E M?
[00:14:43] Lingyin Li: E N.
[00:14:45] Russ Altman: E N P P 1. And of course, anybody who knows biology knows that genes have terrible names. They're long and complicated, but they have abbreviations and we're gonna call it ENPP1. Okay, very good.
[00:14:55] Lingyin Li: Yeah.
[00:14:56] Russ Altman: And you said this is an enzyme that chews up the toxin and therefore the cells around the tumor can't quite tell that it's a tumor 'cause they're not seeing what they're used to seeing when it's cancer, which would be this, this, um, this transmitter that's announcing the cancer. Uh, and so that's very clever of the cancer and it kind of makes sense. It would say, hey, if I can eat up this toxin, I can stay under the radar.
[00:15:20] Lingyin Li: That's exactly right. Yeah.
[00:15:22] Russ Altman: Alright, so what do we do about it? And tell me about your, tell me about your discovery and tell me about how this could eventually maybe even help patients.
[00:15:29] Lingyin Li: Yeah. So, um, we have to know, one question we ask ourselves is that, uh, you know, why do we even have this, uh, mask that chews up this immuno transmitter to begin with, right? So, we have evolved to, um, turn off our immune response, okay? So, I'm gonna take a little bit of a detour, right? Um, which is, um, actually we have not even published this, but I'm gonna let you in a little bit of secret, um.
[00:15:55] Russ Altman: Okay. Just between two of us and anybody who's listening to The Future of Everything.
[00:15:58] Lingyin Li: Absolutely. Um, so, uh, you know, we absolutely need to turn off, uh, immune response against ourselves. As we get a little old, we also leak out DNA from our mitochondria. We also cannot, yes, keep DNA well packaged. So, we must turn on this masking protein to chew up the standard signal so that we don't immunize ourselves against our own neurons. Don't immunize ourselves against our own myelin, for example, right? That's how demyelination happens. So that's why we need this protein. So, it's very funny.
[00:16:40] Russ Altman: So, if I, if I happen to be an older person, this is purely theoretical. If I happen to be an older person, my muscles or my brain or other tissues might release some DNA, kind of by mistake because the systems don't work as well as they used to. That releases this transmitter. And if I'm not careful, my, my immune system is gonna say, oh, this is a foreign agent, let's go kill it. And that would be bad for my brain. Bad for my muscle. And so, this is part of a natural protective mechanism. Okay.
[00:17:08] Lingyin Li: That's exactly right. And I know you love to run, and you love a little suntan. Um, um, as it turns out, uh, UV can actually also break our DNA out of the, our nucleus. And, um, the, the redness that you get, uh, out of suntan is exactly this molecule doing its work. Um, which is why, uh, patients with lupus need to avoid suntan because you already have the ability to recognize yourself. You don't need that additional signal.
[00:17:40] Russ Altman: Okay, great. So that's, that explains why this enzyme's there in the first place and then the cancer takes advantage of it to, uh, evade the immune system.
[00:17:48] Lingyin Li: That's right. Uh, no, cancer is not that smart. Really, it's just whoever happens to have a lot of this mask wins, right? The rest are taken care of by our immune cells. So that's how it works. Um, so then in order to, uh, you know, unmask the cancer cells specifically without unmasking our, you know, neurons that are constantly firing and making mistakes, we must develop tumor specific, uh, inhibitors for, uh, this, this bad mask protein, ENPP1.
[00:18:21] Russ Altman: Okay.
[00:18:22] This is The Future of Everything with Russ Altman. We'll have more with Lingyin Li next. Welcome back to The Future of Everything. I'm Russ Altman and I'm speaking with Lingyin Li from Stanford University. In the last segment, Lingyin told us about the immune system, cancer, and how there are these systems for camouflage that we're beginning to understand so that we can remove the camouflage and expose, especially solid tumors, to the immune system and its full wrath. In this segment, she's gonna tell us exactly how they approach this camouflage system, how they develop new molecules, how they test them, and what's the long-term view for getting these into human trials and ultimately into new medications for cancer. Don't forget, at the end of this segment, we're gonna do the Future In a Minute where I ask Lingyin some rapid-fire questions and she'll give us some quick answers to summarize her view of the future.
[00:19:30] So Lingyin, what are the ways that you have figured out to understand and then intervene with that enzyme that is not being helpful, that is suppressing the signal that would otherwise help the immune system focus its attention on the cancer.
[00:19:46] Lingyin Li: We have figured out that, uh, tumors upregulate, uh, this mask, okay? That's how they become successful. And in fact, the mean, uh, the tumors, uh, meaning they have started on their paths to metastasize. We haven't even touched upon the concept of metastasis, right? It's not the primary tumors that, um, kill patients, typically, right? It's breast cancer that's metastasizing into the lungs, into the brain. Um, so when those, uh, cancers go into a new environment, they must hush, even if they were successful in the primary tumor site, to hush the innate immune detection. They have to do that again. So, we have discovered that, um, uh, metastatic cancers, uh, make a lot more of this mask and need a lot more of this mask. So, which makes it a, a target of our, um, inhibitor or rather drug development.
[00:20:39] Russ Altman: Yeah. So, what, how do you go after this enzyme? It's doing this unhelpful thing. Uh, how can you block it? Do you stop it from being made or do you allow it to be made but then stop it from doing its job? What are the options?
[00:20:52] Lingyin Li: Um, you know, traditionally for enzymes, enzymes are particularly good to target. Easy to target, I should say. Um, so for example, and especially this class of enzyme, by the way, um, this class of enzyme with, um, another enzyme, um, uh, uh, for example called PDE5, um, also degrades a very important signal. So PDE5 inhibitors, um, are inhibitors such as Viagra, okay? What they do is they inhibit the degradation of these key signals so that signal stays on and that's how Viagra works. So, we thought, okay, let's develop this, um, anti-cancer, um, immune Viagra, okay?
[00:21:34] Russ Altman: Yeah. Okay. Immune Viagra. What's not to love?
[00:21:37] Lingyin Li: Right. Um, so, and we do exactly the same mechanism, which is just to put a molecule into where this enzyme is chewing up the immuno transmitter, right? You just stop it.
[00:21:48] Russ Altman: So, you basically block it. It, it clogs up the system.
[00:21:52] Lingyin Li: That's right. That's right. Yeah.
[00:21:53] Russ Altman: And then it can't, it, it can't break down this transmitter, which then sends its signal.
[00:21:58] Lingyin Li: That's right.
[00:22:00] Russ Altman: Fantastic. How do you find such a, how do you find such a molecule? Did you find it or did others find it? How do you figure out, like there's millions of chemicals around the world? How did you figure out the ones that are best?
[00:22:11] Lingyin Li: Yeah, we, um, you know, uh, improved upon existing molecules, uh, that are not as specific and we improved, um, over the years, actually last ten years, uh, we, uh, start to understand what we need in a molecule. 'Cause, you know, uh, what are the new features you want to add to this existing molecule? But I can tell you that, uh, traditionally, uh, what people do is to, uh, just mimic what the, the, uh, immuno transmitter look like. You make something that looks like that, but doesn't have the same function, uh, occupies the same, uh, mouth of the enzyme. And then, you know, that's how the original molecule was made. Um, but, uh, we realized that you want to make this molecule, uh, target specific. So, and how you do that, um, one way, um, nowadays, um, you know, without, uh, getting to, uh, pharmacology too deep, you can make it, uh, irreversible. But that's not what we did, okay? We made this molecule that has a, you know, a very, very long half-life inside the enzyme.
[00:23:20] Russ Altman: So, it loves binding this enzyme.
[00:23:22] Lingyin Li: It loves.
[00:23:24] Russ Altman: And it’s there a long time.
[00:23:25] Lingyin Li: Right. Once it binds, it does not let go, okay? Um, and then we also endow this molecule with, um, high water solubility, okay? What that means is when you inject this into a person or a, a animal, it's going to get fleshed out of your system rapidly. A little bit like the contrast agent in PET scans, okay? So, uh, you know, there you drink this, uh, contrast agent, it flushes out, but it stays in the tumors.
[00:24:02] Russ Altman: Ah, it's because you don't want this molecule, is this because of side effects? You don't want it to be binding the normal enzyme that's doing a good job with like cleaning up the auto, and making sure there's no autoimmunity and, uh, and so you have this little puzzle about how do I make sure it binds the, the cancer for a long time, but that it doesn't cause toxicity throughout the whole body.
[00:24:23] Lingyin Li: That's exactly right. That's exactly right.
[00:24:26] Russ Altman: And that sounds clever. So, the idea is it's very water soluble. It's gonna swish through the system quickly unless it sees this enzyme. And when it sees this enzyme, it's gonna glom onto it and stay there for a long time.
[00:24:39] Lingyin Li: That's right, and also the more enzyme a tissue has, the, the longer it's going to stay because even if it accidentally dislodged from the first one, the next one is going to catch it.
[00:24:51] Russ Altman: It ping pongs around between the different enzymes.
[00:24:54] Lingyin Li: That's correct. Yeah.
[00:24:55] Russ Altman: Okay, great. So that's very exciting. Uh, and now you have, uh, at least one, maybe more of these inhibitors that can stop this process. What do you do with it? Like, what are the first, uh, you must have been very excited. Here you now have this small molecule that you think could be a very powerful kind of, uh, tool for cancer treatment. What's the next step?
[00:25:15] Lingyin Li: Yeah. First you have to show it works in animals and then you have to show it's very safe, uh, in small animals, uh, large animals, and eventually you need to show it is safe in people, which is phase one clinical trial. And then to show its efficacy, which is phase two.
[00:25:32] Russ Altman: And I happen to know that you've recently come out with a paper where you did show, uh, effectiveness, I think in mice.
[00:25:38] Lingyin Li: Yes, that's right.
[00:25:39] Russ Altman: So, what were those experiments? What kind of cancer did the mouse have and what kind of results did you find?
[00:25:44] Lingyin Li: Yeah, we tested this molecule in quite a few cancers and um, was one, um, a common theme we want to pick the meanest cancers, the hardest to treat cancers in solid tumors. Um, so for that, we picked metastatic breast cancers. Uh, we picked pancreatic cancers. Uh, we picked, um, glioblastoma.
[00:26:06] Russ Altman: These are all very scary cancers.
[00:26:08] Lingyin Li: Yes. Yes. So, these are the death sentence, if you will, for cancer patients, right.
[00:26:13] Russ Altman: And did the, did, did the mice get just this molecule or did they get this molecule plus some other cancer, uh, drugs.
[00:26:20] Lingyin Li: Yeah. Um, so no, it's, it's a combination, right? It is a combination. But we combined in a, a very educated way, like I was saying, uh, cancers already emit this, um, immuno transmitter, but giving a cancer, a specific radiation beam can make them make more of this. So, in some cases we combine with radiation therapy. Um, and then, uh, something that we haven't talked about, which is downstream, right? So after, um, we have, uh, uh, blown cancers cover by inhibiting this enzyme. So, this small molecule starts, um, propagating, the T-cells come in, cancers have another great way to tell the T-cells to stop and, uh, that discovery has already won the Nobel Prize in 2018. They're called the adaptive, uh, immune checkpoint blockers, right? Because sometimes we also combine with adaptive immune checkpoint blockers. So together, right, you make more of this an, uh, make more of this small molecule, uh, stop its degradation, bring in the T-cells, unleash their killing power. Um, oftentimes with different combinations, we can get curative effects in these cancers.
[00:27:36] Russ Altman: So, when you say, that's a big word, cure is a big word, as you know, for cancer. And what you mean is the mice has no detectable glioblastoma or breast or, or pancreatic cancer cells left as far as you can tell, looking very hard.
[00:27:49] Lingyin Li: That's exactly right. And we don't just look at the primary site. Uh, for, uh, in the case of breast cancers, we looked, um, in the lungs, we looked in the brains, we looked in the livers, in the bones, and we have no detectable cancers after treatment.
[00:28:05] Russ Altman: Okay. So, in our, in our last minute or so, I have to ask, what is it gonna take to get this to humans? Of course, mice are great, and those results are very encouraging, but we know that there's a lot of stuff that has to happen before we have a drug. Tell me what are your, what is your efforts now, um, to try to bring this to patients?
[00:28:23] Lingyin Li: Yeah, so I almost, um, made a living out of saying, uh, mice are not humans, uh, especially in the case of our immune system. Um, a very interesting point is that, uh, mice lived in a much dirtier environment, so they are more active. So it is, in principle, easier to cure, um, mouse cancers using immunotherapy. And also, they have evolved totally different molecules. So, everything we study, uh, we have to make sure it is well conserved into human immunology. All the compounds we test, we have to make sure it, uh, uh, inhibits the human protein. Um, and then before that we also tested in, uh, in dogs to show its safety. Uh, so now, uh, this molecule has, uh, obtained something called IND status, which means the FDA, uh, has told us go ahead and test it in.
[00:29:16] Russ Altman: Yeah, that's, uh, investigational new drug, IND. So, congratulations. That's a big step.
[00:29:22] Lingyin Li: Yes, that's right. So now, um, that's when the rubber is going to hit the road. So, we do need, um, you know, a lot of, uh, buy-in from VCs and from clinicians to want to sponsor this and run this into clinical trials.
[00:29:36] Russ Altman: 'Cause this is not cheap. 'Cause now we're starting to do human trials. You even have to make sure that you make it in a pure way so that it doesn't have any contaminants and that has to be validated. And then you have to make sure, uh, uh, as you know, toxicity and make sure that, uh, even at a small dose, something terrible doesn't happen. But eventually you get to a clinical trial where you're actually testing, do we see the same kind of results we see in the mouse? How, how many years, what, what kind of timeframe do you see? I know you're putting tons of time into this. Even with all that effort, what's the general like time that it takes to get this to be a, a real drug if it makes it through all of these, um, filters?
[00:30:15] Lingyin Li: Yeah. Typically, we say it takes ten years. Um, but, uh, uh, you know, uh, there is a lot of thought that was put into selecting this target. Uh, and also, uh, a lot of thought put into not just this, uh, therapy itself needs to be safe because it is going to be combined with many other toxic therapies. So, we have, we, we, we've made sure that uh, a combination also is safe, but also, I'm very happy to report that ENPP1 is actually a quite popular target now in pharma. So, we are not alone in this game. Maybe by ourselves it will, you know, take longer for VC buy-ins and clinician buy-ins.
[00:30:54] Russ Altman: And when you say VC, that's the venture capitalists who have the capital to fund all of these studies and everything.
[00:30:59] Lingyin Li: That's right. That's right. But now we have competition, and competition is great for patients.
[00:31:04] Russ Altman: Hey, before we wrap up, I want to introduce you to our new feature called the Future In a Minute. I'm gonna ask you a few questions, kind of rapid fire, and I just like to get you a rapid-fire answer. Does that sound okay?
[00:31:16] Lingyin Li: Yep.
[00:31:17] Russ Altman: Okay. Here we go. First question, what is one thing that gives you the most hope about the future?
[00:31:22] Lingyin Li: It is an arms race between cancer and our arsenal of immunotherapy, so we have to outsmart cancer. Cancers are not getting smarter. We are. And we have figured out a way to blow cancer's covers. We're on the right track and we're going to win this race.
[00:31:36] Russ Altman: What's one thing you want people to walk away from this episode remembering?
[00:31:41] Lingyin Li: T-cells are powerful cancer killers. However, they need innate immune informants. We have figured out a way to tell the informants cancers are there, um, so that they can go tell the T-cells.
[00:31:54] Russ Altman: Aside from money, what's the one thing you need to succeed in your research?
[00:31:59] Lingyin Li: We need talents. I'm not at the bench doing experiments. AIs are not at bench doing experiments. It's our human graduate students and postdocs. We need their buy-in and shows like this, it's wonderful because every time we go onto to a show like yours, we would get flooded with response telling us we're doing a great job. We are heroes to someone. So, we want our viewers, Gen Z viewers to know that we're on the verge of treating late-stage cancers, and this is exciting time to join the workforce.
[00:32:30] Russ Altman: If all goes well, what does the future look like?
[00:32:33] Lingyin Li: In my lifetime, I think each successful therapy is going to give a cancer patient about ten to twenty years of remission. Also, with our new understanding of environmental factors of how to delay cancer, which puts diagnosis, age in a person's late sixties, uh, seventies, then a couple of therapies can get us covered.
[00:32:55] Russ Altman: If you were starting all over again and you needed to get your degree in a different discipline, what would it be?
[00:33:00] Lingyin Li: I think it'll be a medical degree because helping, uh, alleviate patient suffering from diseases will always be my passion.
[00:33:08] Russ Altman: Thank you to Lingyin Li. That was a fantastic set of rapid-fire answers for the Future In a Minute.
[00:33:14] Thanks again to Lingyin Li. That was the future of immunotherapy. Thanks to you for listening to this episode. We're pushing 300 episodes in our back catalog, and you can spend hours, if not days, listening to old conversations, but still good conversations, about The Future of Everything. You can catch me on social media. I'm on LinkedIn, Bluesky, Threads, Mastodon @RBAltman or @RussBAltman. You can also follow the School of Engineering @StanfordSchoolOfEngineering, or more simply @StanfordENG.
