The future of immunotherapy

0:00This 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.

0:37In 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, co-workers as well. It is the 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.

1:08This 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, Ling-Yin Lee 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.

1:43It's the future of immunotherapy. Today, we're going to continue our new future called The Future in a Minute. At the end of our discussion, I'm going to ask Ling-Yin Lee some few rapid-fire questions, and I'm going to 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.

2:14So 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.

2:54And 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, Ling-Yin Lee 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.

3:38Ling-Yin, 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? 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. 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. 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.

4:15It started to cure patients with late stage melanoma cancer. However, it does not work for breast cancer patients. So that's when I started to focus my research on how to make immunotherapy work for solid tumors such as breast cancers. So yeah, you mentioned solid tumors. And I know that in your writing and you're speaking, you talk about how a lot of this immunotherapy, and we have to get back to that because it's a complicated idea. But since we started, a lot of these immunotherapies, their initial success was on blood-borne 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.

4:53So it sounds like there's a special opportunity for solid tumors that makes them different. Yeah, that's exactly right. Right. So we have to understand what is actually the workforce for immunotherapy. It's actually T cells, killer T cells. So these cells engage into one-on-one combat, okay? It literally grabs onto cancer cells and injects its toxin into the cancer cells. So in order for this to work, that T cells must direct the contact of cancer cell. So this is particularly easy when you have circulating tumors because T cells are in circulation. In solid tumors, T cells are not there. Nobody told them they're cancers.

5:31Why would T cells be there? So that's why we work on to bring the T cells into solid tumors. Okay. So I was going to say that in order to really appreciate immunotherapy, we're going to need you to give us a little tutorial on the immune system. And you actually just did that. So an important component of the immune system are these T cells that can kill cancer if they're in the right place. 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.

6:08They 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? Yeah, that's a great question. So as it turns out, our first line of defense, even for bacteria, for viruses, is not T cells. Those are called our adaptive immunity. So typically during bacterial infection, our innate immune cells, they have to recognize these threats within seconds. So how they recognize these threats is through pattern recognition, just like ai okay so bacteria don't look like ourselves um right neither do cancer cells so um for example even though they're derived from our own tissues they don't look quite right 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 on to the surface of a cell, they don't look quite right.

7:08Okay. So then these innate immune cells would put this, these bits and pieces of muted peptides on themselves and then go onto the lymph nodes, 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. Okay. And that works well for the bloodborne ones. But as you were saying, these, these specialty 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 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?

7:51Yeah, this is, you know, the opportunity right now is to basically awaken our innate immune cells to tell them to start picking up these tumors. Socinogens is a big word, but really it's just these muted peptides to pick them up, put them on yourself, just like a decorating crab, okay? And then go inform, become a informant. So this is the most important step. So to do that, we first have to understand how these innate immune cells are even activated. Yes. Yeah, so if you could allow me immunotherapy, You know, in order to talk about the future of immunotherapy, we kind of have to learn a little bit about a history of immunotherapy.

8:33Perfect. Let's do it. Let's do it. Great. Yeah. So, you know, 100 years ago, a doctor named William Cooley was already experimenting with immunotherapy. So he had this observation that a patient with sarcoma got a nasty infection, infected with this strepococcal pyogen bacteria in its bone cancer. And after his immune system warded off the infection itself, the cancer itself also disappeared. So then he started treating patients with isolated bacteria, first with live, and later he killed the bacteria before he injected them into patients to awaken their immune system with mixed results. Okay.

9:17So now a hundred years later, we actually understand the mechanism of that. Basically, bacteria don't look like ourselves, right? So he was injecting these bacteria patterns into the patient and say, hey, wake up. Okay. Don't sleep at will. So now our question - And was the infection in the sarcoma itself? He wasn't injecting later the toxin into the sarcoma themselves, but the original patient, the infection was in the cancer. Okay. Okay. 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 because you need to immunize our immune system against tumors, not against something else, right?

10:05So for that, we had this question, which is how do cancers naturally send out toxin without us injecting toxins into solid tumors? So the molecule cancers actually send out was discovered about 12 years ago now. And this is a molecule which we later, we didn't discover the molecule, we understood how it works, and we later named it as an immunotransmitter. Okay, so now we know that when cancers have mutations, start to collect mutations, or when cancers keep on dividing, they get old, they cannot keep their DNA inside their nucleus where it should be, inside their mitochondria where it should be.

10:52They start to spill out this genetic material. And that's abnormal. Cells normally don't do that, but the cancer is kind of out of control and it's spilling DNA into its body. That's exactly right. Okay. When this DNA was detected inside the cell's body, not well packaged, then we have patent recognition, right? Our innate immune system. We recognize it, and then we make this danger signal, this immunotransmitter, or this toxin, cancer-specific toxin. So we discovered that cancer cells always make this toxin, and this molecule is even more enhanced when we treat it with, excuse me, not immunotherapy, with radiation therapy or with chemotherapy to mess them up even more.

11:41They would spit out more of this immunotransmitter. So this is actually we showed, this is how radiation therapy works, can sometimes elicit a systemic immune response against the cancers, even though the beam was just focused on one tumor to begin with. Yes. Yes. So, so all cancers or virtually all cancers make this molecule that is actually, it's like they're waving their hands saying, I'm a cancer cell. So that seems to be like a good thing for those with cancer, right? Because you could use that. But I think the story gets more complicated. That's exactly right. And, And for the most part, our immune system, our innate immune cells do answer the call from this immunotransmitter.

12:29They go in, right? They respond when cancers emit the signal. They go in. They put a piece and a pieces 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 each t cell that recognizes the cancer would grab up the cancer inject the toxin good good so that sounds like that sounds like a great system yeah this is a great system it works most of the time except when it doesn't great and when is that so that's when cancers we would say have evaded our immune detection and we have discovered one way and a very fundamental way of how cancers um uh break this messaging system uh they put on a mask on themselves it's actually an enzyme that choose up this danger signal.

13:36Okay. So it's as if the cancer knows, and I say no in quotes, but it can, this, the cancer cells, if they keep releasing this toxin, they're going to 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 going to try to kill them if they do release it. I mean, I'm just wanting to make sure I'm following. Is that so far so good? A hundred percent. Yeah. 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.

14:10Yeah. They, um, put on this protein, which chutes up, um, this toxin, this immunotransmitter and this protein, I'm going to mention its name because I'm very proud of it because I purified this protein out of a calf liver. 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? Yes, name and shame. And the name of this protein is EMPP1. E-M-E-N. 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 going to call it EMPP1.

14:55Okay, very good. 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 because they're not seeing what they're used to seeing when it's cancer, which would be this transmitter that's announcing the cancer. 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. That's exactly right. All right. So what do we do about it? And tell me about your discovery and tell me about how this could eventually maybe even help patients? Yeah. So we have to know one question we ask ourselves is that, you know, why do we even have this mask that chews up this immunotransmitter to begin with, right?

15:42So we have evolved to turn off our immune response. Okay, so I'm going to take a little bit of a detour, right? Yeah, which is actually, we have not even published this, but I'm going to let you in a little bit of secret. Okay, just between two of us and anybody who's listening to the future of everything. Absolutely. So, you know, we absolutely need to turn off 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 deep myelination happens right so that's why we need this protein so it's very fun 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.

16:54That releases this transmitter. And if I'm not careful, my immune system is going to 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. That's exactly right. And I know you love to run and you love a little suntan. And as it turns out, UV can actually also break our DNA out of our nucleus. And the redness that you get out of suntan is exactly this molecule doing its work. All right. Which is why patients with lupus need to avoid suntan because you already have the ability to recognize yourself.

17:37You don't need that additional signal. Okay, great. So that explains why this enzyme is there in the first place. And then the cancer takes advantage of it to evade the immune system. That's right. You know, 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. So then in order to, you know, unmask the cancer cells specifically without unmasking our neurons that are constantly firing and making mistakes, we must develop tumor-specific inhibitors for this bad mask protein, EMPP1.

18:21Okay. This is The Future of Everything with Russ Altman. We'll have more with Lingyan Lee next.

18:41Welcome back to the Future of Everything. I'm Russ Altman, and I'm speaking with Lin-Yan Lee from Stanford University. In the last segment, Lin-Yan 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 going to 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.

19:19Don't forget, at the end of this segment, we're going to 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. 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? We have figured out that tumors upregulate this mask. Okay, that's how they become successful. and in fact the meaners the tumors meaning they have started on their past to metastasize we haven't even touched upon the concept of metastasis right it's not the primary tumors that kill the patients typically right it's breast cancer that's metastasizing to the lungs into the brain so when those 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.

20:23So we have discovered that metastatic cancers make a lot more of this mask and need a lot more of this mask, which makes it a target of our inhibitor or rather drug development. Yeah. So how do you go after this enzyme? It's doing this unhelpful thing. 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? You know, traditionally for enzymes, enzymes are particularly good to target, easy to target, I should say. So, for example, and especially this class of enzyme, by the way, this class of enzyme with another enzyme, for example, called PDE5, also degrades a very important signal.

21:14So PDE5 inhibitors 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 anti-cancer immune Viagra. Okay. Okay. Immune Viagra. What's not to love? Right. So, and we do exactly the same mechanism, which is just to put a molecule into where this enzyme is chewing up the immunotransmitter, right? You just stop it. So you basically block it. It clogs up the system. That's right. That's right. Yeah. And then it can't, it can't break down this transmitter, which then sends its signal.

21:58That's right. That's right. Fantastic. 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? Yeah, we, you know, improved it upon existing molecules that are not as specific. And we improved over the years, actually, last 10 years, we start to understand what we need in a molecule. because what are the new features you want to add to this existing molecule? But I can tell you that traditionally what people do is to just mimic what the immunotransmitter looks like.

22:40You make something that looks like that but doesn't have the same function, occupies the same mouse of the enzyme, and then that's how the original molecule was made. but we realized that you want to make this molecule target specific. So yeah, and how you do that, one way nowadays, you know, without getting into pharmacology too deep, you can make it 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. So it loves binding this enzyme. It loves. And it stays there a long time. Right. Once it binds, it does not let go.

23:28Okay. And then we also endow this molecule with high water solubility. Okay. What that means is when you inject this into a person or an animal, it's going to get fleshed out of your system rapidly. a little bit like the contrast agent in PET scans. Okay. So, you know, there you drink this contract agent, it flushes out, but it stays in the tumors. 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 and making sure there's no autoimmunity And so you have this little puzzle about how do I make sure it binds the cancer for a long time, but that it doesn't cause toxicity throughout the whole body.

24:23That's exactly right. That's exactly right. And that sounds clever. So the idea is it's very water soluble. It's going to swish through the system quickly unless it sees this enzyme. And when it sees this enzyme, it's going to glom onto it and stay there for a long time. That's right. And also, the more enzyme a tissue has, the longer it's going to stay. Because even if it accidentally dislodged on the first one, the next one is going to catch it. It ping-pongs around between the different enzymes. That's correct. Okay, great. So that's very exciting. And now you have at least one, maybe more of these inhibitors that can stop this process.

25:03What do you do with it? You must have been very excited. Here you now have this small molecule that you think could be a very powerful kind of tool for cancer treatment. What's the next step? Yeah, first you have to show it works in animals. And then you have to show it's very safe in small animals, 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. And I happen to know that you've recently come out with a paper where you did show effectiveness, I think, in mice. Yes, that's right. So what were those experiments?

25:40What kind of cancer did the mouse have and what kind of results did you find? Yeah, we tested this molecule in quite a few cancers. And with one common theme, we want to pick the meanest cancers, the hardest to treat cancers and solid tumors. So for that, we picked metastatic breast cancers. we picked pancreatic cancers uh we picked um glioblastoma okay these are all very scary cancers yes yes so these are the death sentence if you will for cancer patients right and did the did the mice get just this molecule or did they get this molecule plus some other cancer drugs yeah um so no it's it's a combination right it is a combination but we combined in a very educated way.

26:29Like I was saying, cancers already emit this immunotransmitter, but giving cancers a specific radiation beam can make them make more of this. So in some cases, we combine with radiation therapy. And then something that we haven't talked about, which is downstream, right? So after, you know, we have blown cancer's coverage by inhibiting this enzyme. So this small molecule starts propagating, the T cells come in. Cancers have another great way to tell the T cells to stop. And that discovery has already won the Nobel Prize in 2018. They're called the adaptive immune checkpoint blockers, right? Sometimes we also combine with adaptive immune checkpoint blockers.

27:20So together, right, you make more of this small molecule, stop its degradation, bring in the T cells, unleash their killing power. Oftentimes with different combinations, we can get curative effects in these immunized cancers. 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 pancreatic cancer cells left, as far as you can tell, looking very hard. That's exactly right. And we don't just look at the primary side. In the case of breast cancers, we looked in the lungs, we looked in the brains, we looked in the livers and the bones, and we have no detectable cancers after treatment.

28:04Okay. So in our last minute or so, I have to ask, what is it going to 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 is your efforts now to try to bring this to patients? Yeah. So I almost made a living out of saying mice are not humans, especially in the case of our immune system. A very interesting point is that mice lived in a much dirtier environment, so they're more active. So it is, in principle, easier to cure mouse cancers using immunotherapy. And also, they have evolved totally different molecules.

28:49So everything we study, we have to make sure it is well-conserved into human immunology. All the compounds we tested, we have to make sure it inhibits the human protein. And then before that, we also tested in dogs to show its safety. So now this molecule has obtained something called IND status, which means the FDA has told us, go ahead and test it. Yeah, that's an investigational new drug, IND. So congratulations, that's a big step. Yes, that's right. So now that's when the rubber is going to hit the road. So we do need a lot of buy-in from VCs and from clinicians to want to sponsor this and run this into clinical trials.