303 | James P. Allison on Fighting Cancer with the Immune System

A typical human lifespan is approximately three billion heartbeats in duration. Lasting that long requires not only intrinsic stability, but an impressive capacity for self-repair. Nevertheless, things do occasionally break down, and cancer is one of the most dramatic examples of such breakdown. Given that the body is generally so good at protecting itself, can we harness our internal security patrol - the immune system - to fight cancer? This is the hope of Nobel Laureate James Allison, who works on studying the structure and behavior of immune cells, and ways to coax them into fighting cancer. This approach offers hope of a way to combat cancer effectively, lastingly, and in a relatively gentle way. Support Mindscape on Patreon https://www.patreon.com/seanmcarroll. Blog post with transcript: https://www.preposterousuniverse.com/podcast/2025/01/27/303-james-p-allison-on-fighting-cancer-with-the-immune-system/ James P. Allison received his Ph. D. in biology from the University of Texas at Austin. He is currently Regental Professor and Chair of the Department of Immunology, the Olga Keith Wiess Distinguished University Chair for Cancer Research, Director of the Parker Institute for Cancer Research, and Director of the James P. Allison Institute https://www.mdanderson.org/research/departments-labs-institutes/institutes/allison-institute.html at MD Anderson Cancer Center. He is the subject of the documentary film Jim Allison: Breakthrough https://www.uncommonproductions.com/breakthrough. Among his numerous awards are the Breakthrough Prize in Life Sciences and the Nobel Prize in Physiology or Medicine. Web page https://faculty.mdanderson.org/profiles/james_allison.html Nobel Prize citation https://www.nobelprize.org/prizes/medicine/2018/summary/ Google Scholar publications https://scholar.google.com/citations?user=Vq6NVkAAAAAJ&hl=en Wikipedia https://en.wikipedia.org/wiki/James_P._Allison

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

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• 0:59Sean Carroll?

  Hello, everyone, and welcome to the Mindscape Podcast. I'm your host, Sean Carroll. Cancer is one of the most terrible things we have to deal with in human life. It's a potentially fatal disease, of course. You know, we're all gonna die someday. That's something that maybe we can make our peace with. But unlike many other diseases, cancer seems arbitrary in ways that are hard to pin down. It can happen to anyone. It can happen at any stage of your life. Young people can get it as well as old people. When you reach a certain stage of your life, like I have, not only do you have to worry about checking for it yourself, but you know people who've had cancer and even who have died because of it.

• 1:41Sean Carroll?

  So it's very natural that, as a species, we put a lot of effort into figuring out what is going on, how to stop this. Turns out to be really, really difficult, as maybe you know. Today's conversation is going to be with one of the world's leaders in the field of fighting cancer, James Allison, who won the Nobel Prize a few years ago in physiology and medicine for one of the ways, one of the various techniques that we can use to attack cancer once it starts. The idea being rather than going in and just zapping the cells with radiation or chemicals or whatever, that we can use immunotherapy. In other words, we learn how to cajole the body's own existing immune system to fight

• 2:26Sean Carroll?

  the cancer tumors. And if this can work, it works in some cases, doesn't work in others yet. This is what we're studying and we'll talk about in the episode. But it's, you know, not just a more kind of organic, natural way to fight the disease, but then the person who has had the therapy has that extra layer of protection against getting cancer going forward. You haven't just killed that tumor or most of that tumor. You've built up the body's defense systems. So of course, that is, for real world purposes, a fascinating and important development. For science purposes, of course, it's also fascinating because, man, the body, very,

• 3:05Sean Carroll?

  very complicated, very, very complex networks of reactions and cells and proteins and molecules and all that going on. We learn a lot about it because we are motivated for reasons of making people healthier. But what we learn is also equally fascinating. So we'll talk about how we got here, where we're going, and how I think the impression I get as an interested outsider is real progress is being made on one of the trickiest problems out there. So let's go.

• 3:54Sean Carroll?

  James Allison, welcome to Mindscape Podcast.

• 3:57Speaker 03

  Thank you. Glad to be here.

• 3:59Sean Carroll?

  I guess this is a big topic, right? I mean, you do research on cancer therapies and things like that. Let's start at the very lowest level here. We've all heard of cancer. It's bad, something about cells dividing and going crazy. How do you think about what cancer is, broadly speaking?

• 4:18Speaker 03

  I think it's a plague of a sort that unfortunately involves your own body going awry in some way and a lot of, I don't know, there's a lot of, used to be a lot of stigma associated with it, maybe there still is in some cases, but you know, it's an unfortunate thing that happens to us, you know, we have, we have a lot of cells that comprise our body, if they don't, aren't controlled, it's very, it's amazing to me that it works as well as it does, that everything stays under control, but unfortunately it hits people, it hits a lot of people, way too many, it's hit way too many in my family and.

• 5:02Sean Carroll?

  I guess, I guess the, the question I have is, is it the same phenomenon when we talk about different kinds of cancer, I mean, there's obviously a wide variety, I know some therapies work better than others, is it accurate to call it one thing?

• 5:16Speaker 03

  No, it's not, well, it depends, I mean, the, the common thing is the cells growing where, when they ought not to and where they ought not to, I mean, that's the common thing of all of them, but no, they're very different, they're, they're different tissues, first of all, that's the way it used to be classified, solid, you know, and muscle or whatever, solid tissue versus leukemias, you know, in the blood, and then now it's lung versus, you know, colon or bladder versus prostate or whatever, but then with the advent of genomic sequencing and everything, the tendency was to attribute them to the causation, you know,

• 6:01Speaker 03

  first crudely, you know, carcinogen, obviously carcinogen induced, obviously virus induced or something, although viruses are a tiny fraction, it's not zero, but, but that's not the main thing, but the common thing is just mutation and. Um, the functional classification according to causation can be useful. And for a while, it was thought was the real key. You know, if you know, like, RAS is a molecule that really is involved in a pathway that takes signals outside a cell, like wounding or something, and it tells the cell, oh, you better divide because we need to cover up that scrape or that fix that cut

• 6:46Speaker 03

  or whatever. But if something happens and that pathway gets locked on, you know, so the doorbells ringing all the time, you know, the cells just keep dividing. And the idea was, well, if we could inhibit that pathway, then we cured cancer, right? So this was all the excitement around nearly 2000s, 2010 through 2000, about 2015 was Tars, most of these enzymes that do these things are Tarsine kinases or forms thereof. And so the idea is that you just inhibit that enzyme, you can cure the cancer by attacking the cause. Turns out, good idea, way too simple because the pathways always have multiple steps.

• 7:31Speaker 03

  And you could fix one of them, but then if there's another mutation downstream, you're back to where you started and your drug does nothing. And so that's, that's what the problem is because tumors, as they progress, as the tumors become more and more strange, as they start, they become unstable and the genome actually becomes very unstable and they start, you start getting a lot of more mutations. And as soon as that happens, you have more drivers, they're called. And so you could take one out, it doesn't make any difference. You could cure 99%, kill 99% of the tumor cells, doesn't make any difference because 1% or 0.1% will have another driver and they'll inevitably grow out.

• 8:15Sean Carroll?

  That's interesting. Actually, I don't think I knew that, that the rate of mutation in the tumor gets much larger. So as the tumor is growing, you're not just fighting one kind of cell.

• 8:26Speaker 03

  Yeah, that's not totally universal, but generally it's true that the tumors become, as they progress, become less and less stable. And, um, and, uh, so the idea of having a magic bullet that can attack it at its source is really.

• 8:43Sean Carroll?

  Yeah.

• 8:44Speaker 03

  Was, was. Not unreasonable and it was impossible to even think of doing anything about it until we had genomic sequencing, which we do now, but now we know it's probably not going to be, it's certainly worth doing because it can prolong life. I've always, as an immunologist, tend to look at things differently because the tumor biologist, you have to take the classical tumor biology view of cancer would say, oh, well, you got that mutation, let's attack it and, and, and we'll be done. So we should concentrate on what's going on there. On the other hand, so the, there's lots of mutations. The mutations

• 9:26Speaker 03

  really occur pretty much randomly. It's when they hit, you know, so they got to hit generally a couple of genes before you got problems, a couple of very types of genes that are very specific. But the other ones, the cancer biologists say, oh, well, those are irrelevant. They're passengers. They're not important because they're not drivers. The immune system, on the other hand, you know, trained as an immunologist, your immune system is just, its purpose is to find things that shouldn't be there.

• 9:57Sean Carroll?

  Exactly.

• 9:58Speaker 03

  They don't care what they do, you know, that shouldn't be on my cells. That's, that cell may have a virus in it. I'm going to kill it, you know? And so then you look at it that way and those mutations, which the cancer biologists are not important because they're not the drivers.

• 10:19Sean Carroll?

  Yeah, okay.

• 10:19Speaker 03

  They're equally important to the immune, immune system.

• 10:22Sean Carroll?

  Immunology.

• 10:23Speaker 03

  The immune system doesn't know the difference. It just goes, there's something different here. We better get rid of that guy.

• 10:28Sean Carroll?

  Well, you already mentioned that it's a little bit surprising to you that the body lasts as long as it does and works as well as it does. I mean, I can, I see that and I also see someone else saying, it's kind of amazing to me that bodies haven't learned to fight cancer better since it's all over the place.

• 10:45Speaker 03

  Yeah, well, evolutionarily, you know, it's all evolution and unless it takes you out before you reproduce, there's, evolution doesn't care. You know, if you get cancer when you're 50, evolution doesn't care.

• 10:56Sean Carroll?

  Right.

• 10:56Speaker 03

  Doesn't matter.

• 10:59Sean Carroll?

  But some animal species are pretty good at avoiding cancer. It does seem to be possible. Do we understand that?

• 11:05Speaker 03

  No, no, of course we did. No.

• 11:09Speaker 03

  Maybe they have a really good immune system. I doubt it.

• 11:13Sean Carroll?

  This is very vague to me. Isn't there some paradox that larger animals you might expect to get cancer more easily because there's more cells, but in fact they get it more rarely?

• 11:24Speaker 03

  Yeah, no, that's true. I guess elephants, though, as far as I know, elephants don't get cancer very often. But then again, maybe they're not exposed to carcinogens like we are.

• 11:34Sean Carroll?

  That's true, but mice happily we're able to give cancer to because we that's where we do a lot of our tests.

• 11:39Speaker 03

  Not so good for the mice, but.

• 11:42Sean Carroll?

  So how much do we know about? I know this is not you. You sort of just very nicely explained why this is not what you care most about, but how much do we know about how tumors start? And is there? Is it just a myriad of various different reasons? Or is there some central understanding?

• 11:59Speaker 03

  Well, there's there's some central understanding. I think what it comes down to, if you look at all the data that exists, is that it's basically mutations that cause it and and

• 12:09Speaker 03

  if you get out of the sun a lot and you expose your skin to ultraviolet radiation, that chances are you're going to get mutations in your skin.

• 12:19Speaker 03

  They can cause melanoma. Because that's, you know, what the sunlight hits and and you know, stay out of the sun, you're probably not going to get melanoma, although plenty of people say lung cancer, you smoke. You know, you're highly, you know, you're a lot more likely to get, but you're not that if you don't smoke it, I mean, you're not going to get lung cancer. Because the cells divide, there's there's there are mistakes.

• 12:46Sean Carroll?

  And you're obviously going to tell us about immunotherapies, but maybe put that in the context of other kinds of therapies. I mean, we've all heard of chemotherapy, radiation therapy, etc.

• 12:57Speaker 03

  Let's go back historically. Let's go. Let's go back way to the start, you know, there's evidence in that the Greeks, you know, knew about tumors and they cut them off.

• 13:08Sean Carroll?

  Okay.

• 13:09Speaker 03

  And so the very first cancer therapy was surgery.

• 13:13Sean Carroll?

  Got it. Yes.

• 13:14Speaker 03

  And that still is perhaps the most effective if you can get it all. That's the problem, though, because by the time you certain kind of cancers in particular, like melanoma, very often by the time you notice it and then you're kind of big way, it's already spread to other.

• 13:30Speaker 03

  Organs in your body, prostate, same way.

• 13:35Speaker 03

  So.

• 13:37Speaker 03

  But if you can catch it early, surgery is pretty effective. The next therapy that came along was radiation. You know, the Curies around the end of the 19th century,

• 13:47Speaker 03

  beginning of the 20th century. Madame Curie in particular, developed radiotherapy. And, you know, that was quite useful and curative in some cases. Of course, it also caused cancer, you know.

• 14:06Speaker 03

  People learned

• 14:09Speaker 03

  by its biogenic effects. But the idea was you blast a cell and give it enough mutations that it can't live. The problem, of course, is that it also kills the normal tissues. So you gotta be careful about that. And then oddly enough, with the advent of mustard gases and things during World War I and chemical warfares, agents that were developed leading into World War II, ultimately led to some pioneers in cancer therapy in the 50s, you know, applying it to leukemias, childhood leukemias in particular. Mustard, I mean, just, it's toxic gases that, toxic chemicals that were used to mustard gas, for example. Those were the basis of the first chemotherapies.

• 14:53Speaker 03

  They kill dividing cells.

• 14:56Sean Carroll?

  Why are they good at killing cancer cells?

• 15:00Speaker 03

  They cause a lot more mutations, you know, as they screw up the DNA as it's dividing and making sure that the cell can't successfully divide without.

• 15:11Speaker 03

  Unfortunately, you could also put in a lot of mutations that'll make you more likely to get a cancer down the road, too, you know. But, but they also, but the bottom line with that, with both of those, both radiotherapy and chemotherapy as given.

• 15:30Speaker 03

  Unless you kill every last tumor cell with those techniques, those approaches to it, the tumor is going to win because it'll just come back. And so you have to blast them so hard or with radiation or poison them so much that it makes you sick, your hair falls out, the lining of your gut comes out, you don't make new blood cells, your immune system's blown away, you know, and you're sick. And that's, you know, that's, that's what I saw when I was growing up and my mother and two of her brothers and my brother. And it's, it's, it's, uh, you know, it's, it's, it's a devastating thing. Not just the cancer, but the consequences of the therapies.

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• 17:13Sean Carroll?

  And do tumors spread just because the cells in the tumor sort of get carried around by the blood system? Or?

• 17:21Speaker 03

  It's a little more complicated though, Matt. They're, they're...

• 17:26Speaker 03

  There are signals that tell them to stay where they are. Those could be lost. But they can also develop things on their servers that'll tell them, "Well, you really belong over here," you know?

• 17:36Sean Carroll?

  Okay.

• 17:36Speaker 03

  So it'll leave. I mean, that's the way they get theirs through the blood, but it's more complicated. There has to be changes that allow them to get into the blood and other changes that allow them to get out of the blood into the tissue that they're going into. So that's a whole nother area of metastasis of study that's underwriting a lot of it.

• 17:55Sean Carroll?

  And my understanding is that you started as a chemist, an actual chemist, more than a sort of biologist or medical person?

• 18:03Speaker 03

  Yeah. Well, a biochemist. I got bored with chemistry, biochemistry quickly. And actually then when I was, but again, I had this family history of cancer, which made me, I was interested, ultimately, I was interested in biology. Started in biochemistry because that's just, I don't know where I landed. But then as I learned about the immune system, T-cells had just been discovered shortly before I was an undergraduate and I was really fascinated by the whole idea of the immune system. But it was mostly antibodies and B-cells at the time, but then when T-cells came along,

• 18:45Speaker 03

  I happened, I was lucky enough to have an immunology course as an undergraduate at University of Texas at Austin. And Bill Manning, the professor, towards the end, he was an antibody guy. Towards the end of the semester, he talked about these new cells that have been discovered called T-cells that percolate all through your body. It was known, you know, they go all through your body. I mean, not only just going around in the blood and the lymph, but they actually go through your tissues.

• 19:14Sean Carroll?

  Okay.

• 19:15Speaker 03

  Screen your cells and see what's going on. Every of the remotest corner of your body, you know, is being surveyed.

• 19:24Speaker 03

  Uh, surveilled, I guess the proper verb. Um, by, um, by the immune system to make sure nothing's going awry. And that's one of the reasons we're able to keep it all together without going completely bananas. You know, one of the reasons early on, first of all, most of the mechanisms for replicating are pretty damn accurate. But if they're accurate 99.9% of the time, that's not enough.

• 19:48Sean Carroll?

  Not enough.

• 19:49Speaker 03

  You're gonna get problems.

• 19:51Sean Carroll?

  And T cells are, they're a variety of white blood cells?

• 19:56Speaker 03

  Yeah, yeah, a variety of them. Yeah, these, uh, lymphocytes are one kind, but they're also macrophages. They're largely, I guess I would say two families of them, lymphoid cells and myeloid cells. Myeloid cells are like macrophages and things like that, that engulf bacteria or infected cells or dying debris from dying cells and clean up wounds and all that stuff and help wounds repair.

• 20:24Speaker 03

  And they, and they have innate signals, they're called, that they can recognize a lot of viruses, a lot of bacterial, just because they have carbohydrates and things on their surface that is classes of molecules are different than those found in our cells, mammal, mammal, mammalian cells. So they're sort of this, we call them innate because everybody's got those and they can protect you against a lot of organisms. But that's not enough either. And so late evolution with development of, actually not shortly, shortly after vertebrates and things. But, but anyway, evolutionarily, this other system came on, which we call the adaptive immune system,

• 21:09Speaker 03

  where you actually have receptors that are made

• 21:15Speaker 03

  by random recombination of DNA sequences. I don't want to go into the details, but basically essentially random process. They give you a random set of different receptors. It's been calculated that you can make all things, if you had full ability to make.

• 21:35Speaker 03

  Every receptor that can be made with the structures that are in there. It's really a fascinating area of biology that. And it's on, but it's 10 to the 15th, maybe 10 to the 17th power.

• 21:51Sean Carroll?

  Yep.

• 21:53Speaker 03

  You only have about 10 to the 10th cells.

• 21:57Speaker 03

  10 to the 12th cell. So it's a thousand times more cells than total cells, at least a thousand times more total cells than you have in your body. So each of us really realize only a fraction of the possible diversity of different T cell receptors that could be made in your body and to the species, you know. So, but sort of the, the population is protected probably, but not the individual necessarily.

• 22:26Sean Carroll?

  Well, I was gonna ask, do the T cells in our body develop new receptors? Do they learn on the job or does the body make new?

• 22:36Speaker 03

  No, they're generated essentially randomly.

• 22:38Sean Carroll?

  Okay.

• 22:40Speaker 03

  Um, these cells come out of the bone marrow. For T cells, they come out of the bone marrow. They go to this organ called the thymus, which sits right above the heart. And there they start developing from this precursor stem cell into the, into functional T cells by random rearrangements and they're put together. And there's this fascinating testing system where there's a scaffold on cells that presents the antigens, which are little bits of protein that are only eight to 10 amino acids, eight to 12, maybe amino acids long, that are presented in the surface of this thing. It looks like a hot dog bun. And it's got a peptide in the middle of it.

• 23:22Speaker 03

  It's, that's, there's a peptide for virtually every protein that's made in your body. It'll bind there and it's been, will be put on the surface of your cells. So the immune system knows a sample of everything that's going on in the cell. Even if the thing normally wouldn't be on the cell's surface. If it's a virus that's just infected a cell and the cell starts making bits of virus.

• 23:48Speaker 03

  I mean, making the parts of the virus that it needs to reproduce and grow out and affect other cells. As they're making it, those proteins will be cut into little pieces and pieces that will be put on the surface. And the right T cell comes by and says, whoops, that shouldn't be there, it'll kill it. It's essentially random.

• 24:07Sean Carroll?

  So the cell is sort of doing its own annual checkup at all times.

• 24:13Speaker 03

  Exactly. But you gotta get rid, a lot of those are gonna be harmful. They may be harmful and so they gotta, the tumor, I mean, the thymus not only educates the cells as to which ones can be useful, but gets rid of the ones which will hurt you, hopefully. If they don't, you end up with diabetes or you end up with, you know, different autoimmune syndromes and stuff.

• 24:37Sean Carroll?

  So, sorry, these are T cells that can be dangerous if they're not in the right kind?

• 24:41Speaker 03

  Yeah, if they're auto reactive, they react with self-proteins. Or sometimes if a virus comes in and tricks the immune system into thinking something's foreign, when it's closely enough to a self thing, occasionally you'll get a spillover, can be damaged, like for measles and stuff, you know, down the road. But, but anyway, basically, they're pretty damn good, though.

• 25:05Sean Carroll?

  Yeah. This is where my simple physics brain rebels at the complexity of all the networks inside the human body. It's kind of an amazing edifice.

• 25:14Speaker 03

  Yeah, how many stars are there?

• 25:16Sean Carroll?

  Well, there's a lot of stars, but stars are pretty similar to each other. There's 10 in the 22 stars out there, but, you know, they're, they're not that different. There's no lock and key in there. I mean, I guess that's my question, that, that your talk about receptors reminds me of people who are trying to study smell and how, you know, we're, we're sensitive to different kinds of molecules. Is it a similar kind of thing going on?

• 25:40Speaker 03

  Yeah, in a way, except that there, what, what you have is one kind of receptor for each kind of.

• 25:48Speaker 03

  Bit of a smell. And it's the sum of all those that tells you what the overall smell is. But each one only detects one thing and the brain integrates it all.

• 25:57Sean Carroll?

  Yeah.

• 25:58Speaker 03

  Because here you've got all these different ones that are flowing all around. All you need to do is trigger one and.

• 26:05Sean Carroll?

  And so the job of a T cell is to understand what the normal, healthy cells are like and, and target anything that is not that.

• 26:13Speaker 03

  Exactly. Not self recognition is what it's called. Very philosophically, a very, how do you recognize not self?

• 26:22Sean Carroll?

  But they do a pretty good job, like you said, and yet we still get cancer. So there's some reason why, I guess in principle, they can attack cancers, but they don't do as well as they could.

• 26:34Speaker 03

  Yeah, that's first of all, because the cancer cells are not necessarily all that different. Early on especially, although they get weirder and weirder with, with, with time and, and often with a lot more mutations. But they also have ways of protecting themselves because cells don't like to be killed either. For example, in tumor cells, there's a process called apoptosis. And there, there are mechanisms that guard, cells built into the cell are mechanisms for detecting mutations. If there's too many, the cell tries to commit suicide. It's told to kill yourself because you're going to get, may cause cancer.

• 27:18Speaker 03

  At least that's the, the thought. But there are these suppressor genes which do that. So really, in order to get cancer, you've got to not only get an activating gene, which will tell the cell it ought to be a cancer, but you've got to get rid of those suppressor genes which would shut that down. So genetically, it's complicated too, because you really have to have both.

• 27:41Speaker 03

  In order to get it, so that's why some people with retinoblastoma gene, for example, if you have two copies of that, kids get tumors of the eyes when they're about two years old. It's a devastating disease. But in other kinds of cancer, you don't get them in your germ line, but you can get them in your somatic cells. And if you lose the RB genes, that makes you a lot, in a cell, that makes that cell a lot more likely to get cancer to.

• 28:11Sean Carroll?

  That helps because I did have the question, you know, do tumors or do cancer cells defend themselves? You know, they don't, they don't pass on their genes in some sense. But I guess the answer is, but they're versions of or made of ordinary cells, which do have defense mechanisms.

• 28:29Speaker 03

  Yeah, yeah. And they also, one of the things that we found recently, that's even more interesting to me is that the immune system, every now and then, you know, these macrophages who play a role in cleaning up after wounds and wound healing and replacement, they'll protect the tumor too.

• 28:49Sean Carroll?

  Oh, okay.

• 28:50Speaker 03

  The wound. And so your own immune system can turn around. And we're finding that that's a re, one of the reasons, that happens big time in, in pancreatic cancer and, and in, um, um, glioblastoma, you know, which are tumors that are very lethal. And we, we're still, we got the, it's not that we got the T cell issues solved with those, but what we know is there are myeloid cells there that are trying to stop the T cells from killing the tissue because they're just doing what, that's their normal function is to protect tissue and help it heal. They just happen to, you know, they get in a weird

• 29:32Speaker 03

  situation where they are treating the tumor like a wound and protecting it from the immune system. So that's one of the things that we're working on now is trying to find out some way to override that or change the myeloid cells where they'll help, they, they could also help the T cells. This depends on what they're doing. It's a whole new area of biology that that single cell RNA techniques and things are making us realize that you talk about T cells, you know, there used to be B cells and T cells. Now they're T cells specifically. First, there were two kinds, then there were five kinds. Now there are about seven kinds. The truth is that those kinds are just constructs that we make up.

• 30:15Sean Carroll?

  Yep.

• 30:16Speaker 03

  In biology, it's a continuity, you know, it's just a continual spread. In myeloid cells, it's really pronounced. You could see all these different cells. They differ by two or three genes that are being expressed. And you could just shift the population one way or another. And that's what we're trying to figure out. And then shift them from this protective overall effect to the helping, you know, thing to help the immune system rather than hinder it. So.

• 30:42Sean Carroll?

  One impression I get from reading about these or talking to people is that everything is about switches, turning things on and off, you know, like once you realize that every cell has the same DNA in it, I guess it makes sense because they do very different things, but it's all a matter of which parts of them are playing a role at this particular moment.

• 30:59Speaker 03

  Which genes are turned on and how much? And it's the relative amounts of different genes in some cases. The complexity is amazing. And so, you know, our brains cut and box things, but nature doesn't.

• 31:13Sean Carroll?

  How much, you know, it sounds like with the receptor stuff on the on the wall of the T cell, that's, that's right down to the level of atomic and molecular structure, right? Is it, is it very different how we're studying that now than when we were in like 1980s or whenever it was? Like, has the technology changed things?

• 31:35Speaker 03

  Well, yeah, I mean, in the seventies, nobody knew what the T cell receptor was. I mean, that was my first thing when I got interested in immunology was what is the antigen receptor? What is it that the T cell uses? And nobody knew what it was. And so I put on my biochemist hat and said, well, what should such a molecule look like? And worked it out and, and published that for the first time in 82. It's gonna look like this and I had data and stuff and then the genes were cloned a couple of years later and confirmed that that's, that that's what it was, an alpha chain, a beta chain, two, two chains of protein, both of which have constant regions and then variable regions.

• 32:18Sean Carroll?

  Hmm.

• 32:18Speaker 03

  And outside it gives you the combining set. Uh, but how, how is it presented? And so there was this. I, I won't go into the details too much, but that's another complicated thing, how the molecule, that hot dog, it doesn't, you know, every weiner won't fit into that bun, you know, everybody's bun's a little bit different, holds a different kind of weiner. And so, you know, if you've got the right, you know, bun for the peptide, you could present it, if you don't, you won't. So, you know, that's another, if you can't present a peptide, even though it's there and it's from a cancer, then the T cells aren't gonna see it.

• 32:58Sean Carroll?

  We don't, we don't mind a little bit of details here. You're allowed, like, if you really wanna go into details, we'll, we'll go with you a little way.

• 33:05Speaker 03

  Okay, well, I won't go anymore, but it's, but it's, it's a complicated thing. But we didn't know this stuff until the eighties, the nineties, and now it's, we're beginning to understand.

• 33:13Sean Carroll?

  Yeah.

• 33:13Speaker 03

  Some detail and now with, um, um, a lot of the work in, in terms of really understanding the biology of it, some of this, um, the new work from the Nobel Prize, this David Baker, for example, and understanding, uh, how to, how sequence informs shapes and how shapes influence sequence, all this, we're beginning to understand at the molecular level, you know, how these interactions occur and how to manipulate them a little bit better in ways we couldn't even think about 10 years ago, much less in the eighties.

• 33:54Speaker 01

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• 34:22Sean Carroll?

  I do love the idea that even before you really had any direct evidence of what it looked like, you could sit back and think, well, what should it look like to do the job that it does? You know, in some sense, that's what people did for DNA, too.

• 34:34Speaker 03

  Yeah, I'm one of these old school guys that thinks hypotheses are useful.

• 34:37Sean Carroll?

  Yeah.

• 34:39Speaker 03

  Now it's get a whole bunch of data and try to pull something out of it, you know?

• 34:43Sean Carroll?

  Well, can we, are we at the level now where we take pictures of not just T cells, but the actual receptors that are on them?

• 34:51Speaker 03

  Yeah, pretty much. Pretty much.

• 34:54Sean Carroll?

  Those are the things that have 10 to 17 different possibilities.

• 34:56Speaker 03

  That's, that's really helping with vaccine design.

• 35:00Sean Carroll?

  Right.

• 35:00Speaker 03

  And stuff now. So we're on the verge of being able to, in some cases, develop prophylactic vaccines, I think. Certainly for HPV, we're there. We can prevent, we can prevent HPV-induced cervical cancer and, and head and neck cancer by, by the HPV vaccine if it was, people would just use it. The more importantly, in the clinical realm are therapeutic vaccines now. And we understand, we're beginning to understand enough about the antigens that are induced by the mutations where we can begin to come up.

• 35:42Speaker 03

  This was something we was greatly informed about the, by the, um, um, our, our recent epidemic, you know, with, with, with, with the, um, virus, with the vaccine strategies that were developed there and where you've got basically a cassette approach now where we know how to really put a gene in the middle of this cassette. I mean, they're, they're gonna, we're gonna, they're gonna, I think we're gonna come up, there's gonna be eventually. A small set of adapters, you know, you could use. It'll have all the signals that you need to properly activate the innate immune system and all that.

• 36:24Speaker 03

  But you put your specific thing in the middle of it and we can generate a vaccine in weeks.

• 36:31Sean Carroll?

  Pretty good. I mean, is this, is this part of the sort of CRISPR revolution of gene editing?

• 36:38Speaker 03

  That's part of it.

• 36:39Sean Carroll?

  Yeah.

• 36:39Speaker 03

  Part of it, being able to get the genes out. It's more useful right now in testing is whether you're right by actually doing fine structure, seeing if you can initiate or terminate an immune response by.

• 36:51Sean Carroll?

  Okay.

• 36:51Speaker 03

  You know, manipulating things. But, but yeah, it's that and, and, and just all the work that went in developing about the coronavirus vaccines, the COVID vaccines. But that, that's sort of framework. It's not exactly the same thing, but it'll be something very similar, which now you can theoretically take a melanoma patient, sequence the genome and with computer algorithms, predict which of the mutations would actually elicit in your own body because different peoples, it's called MHC type, the genes that you have that influence what you present. If you know that and you know the sequence of the different peptides, you can predict

• 37:36Speaker 03

  which ones will be presented and then you can decide the proper vaccine to snap it into that thing and start vaccinating people. So that's, that's coming along. I think that preventive vaccines, pretty soon we're going to be able to maybe protect people that have what's called, oh, what is it? Lynch syndrome, they get a lot of polyps, you know?

• 37:58Sean Carroll?

  Oh, yeah.

• 37:58Speaker 03

  Eventually go on and develop colon cancer. It's definitely predisposition, you can predict. But there are mutations, common mutations associated with that, that I think if you immunized early enough, you could protect those people from ever developing the disease by immunizing them later. Maybe the same will happen with BRCA. You know, BRCA mutations are associated with, in women with breast cancer and ovarian cancer and men also with certain kinds of cancer, but it may be possible to prepare vaccines there. But most of the times the mutations are so individual.

• 38:38Speaker 03

  Individually specific to you that there's no way you're gonna have a vaccine you can prophylactically treat the population for most cancers, you're gonna have to come up with something that's really powerful and allows you to jumpstart a response as soon as you detect it. And I think we're getting close, we're not there yet, but.

• 38:56Sean Carroll?

  But I was actually gonna ask about the role of simulations. I mean, as a, in physics and astronomy, of course, that's what we do all the time. We simulate things, we test them against the data. I've always had the impression that in biology, the state of the art was that biological things are too complicated to do that and too specific and too individual, so we have to actually test the pharmaceutical in a living thing rather than just putting it on a computer.

• 39:21Speaker 03

  Yeah, I mean, we're still there, although it's better now, we could guess. We can make educated guesses now. We can't get exactly there, but.

• 39:34Sean Carroll?

  So, okay, so we have this basic security force in our body of the T cells roaming around looking for interlopers. You mentioned a little bit about this already, but why is it that they aren't better at attacking cancer and how can we make them better? That seems to be the project, right?

• 39:52Speaker 03

  Yeah, well, again, it's because one of them is big and it's that largely they're individual. So your tumor has mutations that nobody else has. So you gotta tailor it to the individual. And secondly, there are, there are ways that the tumor can lose. For example, the peptide has to be from the, from the, containing the mutation, has to get on the cell's surface by these MHC molecules. And if you lose expression of MHC molecules, then they're invisible to the immune system. The tumor will still be there, still making. The mutation will still be being made, but the immune system can't see it because it doesn't

• 40:35Speaker 03

  get to the surface of the cell. There are ways around that that we've got to have them, but that but that's what happens and has been shown in melanoma, for example, patients.

• 40:44Sean Carroll?

  Okay.

• 40:46Speaker 03

  Just quit making the molecule that carries it. But there are ways, there are other ways around that that we're beginning to come up with. But but that's one easy mechanism. Another one is that one of the main ways that tumors kill tumor cells is by making gamma interferon, which is a cytokine that, I mean, you've heard of, but what are its activities besides helping protect you against viruses? It'll causes tumor cells to quit dividing and can kill many of them. But if you lose anything along the receptor downstream of the gamma interferon, the thing that detects gamma interferon and tells the cell it's around, if you mutate anything in that pathway, then that doesn't work anymore either. And

• 41:30Speaker 03

  so the T cells can make all the gamma interferon they want, the tumor won't, you know, won't respond to it. So there's that too. So.

• 41:41Sean Carroll?

  So so what is our goal as immunotherapists? Are we trying to teach the T cells to ignore some of these?

• 41:49Speaker 03

  Well, no. Well, first is just to get the T cells.

• 41:52Sean Carroll?

  Yeah.

• 41:53Speaker 03

  That's the and then secondly, an importance is there's something about the myeloid cells, which we're not there yet. We're getting close on the T cells. The myeloid cell, we're only beginning there. But ultimately, it's how do we deal with these things that that comes down? So it's not that you could get the T cells to do any better, but you could come up with ways of making them work at a distance, you know, it's kind of hard to explain, but a different type of T cell, they'll like more soluble factors, maybe see the antigen on a myeloid cell, even though the tumors can't present it. If these myeloid cells, which will be gobbling up or tumor cell dies, they'll pick up pieces of it,

• 42:37Speaker 03

  put it on their surface. If they have the antigen and a T cell sees it there, and they can make enough of these gamma interferons or other things, then they can kill the tumor cells at a distance, even though they don't they don't interact physically directly with the tumor cell anymore. I mean, that's.

• 42:54Speaker 03

  We can show that happens in animal models, at least I'm pretty sure it happens in people as well.

• 42:58Sean Carroll?

  Okay, I mean, I read a little bit about the T cells before talking to you, but I didn't read anything about myeloid cells. Maybe you should tell me something about that. It sounds like they're important.

• 43:07Speaker 03

  Yeah, that's, well, the reason, I mean, I, I, I used to avoid the things like a plague because they're so complicated. There's so many different types and, but what we found, started what, I mean, we, I'm speaking there, not as just me, but the field began to realize is the tumors which don't respond well to T cell based therapies usually have really large populations of myeloid cells in them. So that raised the hack, you know, raised the interest and sure enough, you can show that the myeloid cells can inhibit T cells. And we've, we've found two molecules on myeloid cells that do that. And we've shown if you take them away, then we can make the T cells more effective. So

• 43:50Speaker 03

  that leads to rise to some more strategies where you target the myeloid cells, but you're going to have to do both, particularly in things like pancreatic and glioblastoma.

• 44:01Sean Carroll?

  What, what are the myeloid cells? What's their role when everything is going well?

• 44:05Speaker 03

  Uh, gobble up bacteria that come in.

• 44:10Speaker 03

  Deal with if antibodies have, if you've made antibodies and they're binding to viruses or bacteria and clumping them up to gobble up get rid of the bugs that way. Um, as I said, to wound heal, to help wounds heal or

• 44:25Sean Carroll?

  Okay, good.

• 44:26Speaker 03

  Make growth factors and stuff, you know, just sort of generally handy men. You know, they're just sort of general handy men that do whatever fixer uppers or you need, um, but they can get in the way.

• 44:40Sean Carroll?

  And they have this spin off effect that they can basically communicate the existence of a tumor to the T cells?

• 44:47Speaker 03

  If you trigger them right, yeah. Or they can, or they can hide them from the tumor cell too. They can hide the tumor cell from the T cells too.

• 44:55Sean Carroll?

  Right. If things are going badly. And isn't there also, this is my, my very vague understanding popping up, but you can get in trouble if you make too many T cells.

• 45:05Speaker 03

  Yeah. If you make too many T cells, you can definitely get sick and. And especially if they react with normal cells or were something that makes big soluble factors that affect. And that that unfortunately is one of the main side effects of of the therapies is cross reactivity with normal tissues and things. But I mean, there's no free lunch, you know, you start messing with those things. I mean, most, I mean, it's not, it's not that it always happens. I know of at least one marathoner who got melanoma and went through the whole course of therapy and never missed a race.

• 45:45Sean Carroll?

  Oh, wow.

• 45:46Speaker 03

  You know, other, other people are getting very sick and sometimes there can be things which can be fatal. Thank God, they're, they're rare. And the clinicians now know from experience, just developed algorithms for recognizing when it's about to happen and heading it off or at least reversing it early on while you've still got time.

• 46:07Sean Carroll?

  And by the therapy, I mean, it sounds like what we're doing is sort of trying to regulate the amount and the sensitivity of these different cells in our immune system, presumably by giving people drugs?

• 46:20Speaker 03

  Drugs in the form of, right now, one of the popular things are antibodies. These are just proteins that we can make that are very specific. I mean, that's what we did with C T L A four in the, in the nineties, you know, there was this molecule and it was funny, it looked like a molecule that was the gas pedal of T cells, but see this molecule called C T L A four, and we showed that it was actually not a gas pedal, it was a brake.

• 46:48Sean Carroll?

  Ah.

• 46:49Speaker 03

  And there's the people that called it a gas pedal. What they did was they had T cells that put them in culture, activate them and then add an antibody and they'd get more. And they said, okay, well, that's a gas pedal. That's what we did early in the eighties, showed that C D twenty eight is another molecule. It's like the gas pedal. So the antigen receptor you could think of is the ignition switch. That's all it is. It tells a T cell, but a T cell has to get a second signal at the same time, which is the, like the gas pedal, and that's a molecule called C D twenty eight that we showed in the, in the late eighties, you know, was the gas pedal. If you don't push on that.

• 47:31Speaker 03

  Accuminating through the antigen receptor doesn't do any good at all, or T cells don't do anything. Tumors never have, um, there's solid tumors, I should say, don't have the structure that binds to that gas pedal. So it's complicated. So tumors are inherently, solid tumors are invisible to the immune system because they don't have that second signal. The only way they get them is to the tumor, and we worked this out in the early nineties, the tumor gets big enough or whatever causes inflammation, the innate immune system comes in, the innate immune system has those things that called, they're called B7 for, they can

• 48:12Speaker 03

  be called Frank, it doesn't matter, I mean, it's just, the name means nothing, but they bind to CD28 and that's, that says go. So, the only way that the immune system with solid tumors, and this is, we published this in the early nineties, was, uh, when you, that they grow until there's tumor cell death, and the innate immune system comes in and primes the T cells, and then you start generating T cells. But the thing is, you probably got 10 to the 10th, 10 to the 9th, different, nobody really knows for sure, but different T cells in your body with different receptors.

• 48:54Speaker 03

  And of course, that means you've only got a few hundred, maybe, of any given clone. And that's not enough to protect you against anything, you need hundreds of thousands. And so you have to, they have to expand. And so that's what this, so the T cell receptor sees the, you know, ignition switch, and then when you, but nothing happens really until you push on the CD28 molecular gas pedal, then they take off, you gotta generate a hundred thousand, I mean, you've got hundreds of thousands to millions of cells to swarm through the body and look for things. That's what's so cool about, because then you don't need to know where to cut, or know

• 49:35Speaker 03

  where to shine the radiation or whatever, you let the T cells go find it, go find the micrometastases, you know, the little clumps of tumor cell under your toenail or wherever.

• 49:48Speaker 03

  I mean, that's exaggerated. But anyway, they go find the tumor cells wherever they are and take them out, or at least keep them in control while they don't grow anymore. But that process has to happen fast or the tumor wins.

• 50:06Sean Carroll?

  And so tumors are going to grow very fast generally, yeah?

• 50:08Speaker 03

  Right. And see, well, they not that fast. It takes years generally. It's at the end where they start damaging.

• 50:15Sean Carroll?

  Oh, okay.

• 50:16Speaker 03

  That's the problem. I mean, a lot of tumors could get quite large as long as they don't aren't in a place. I mean, you got a lot more degrees of freedom in a tumor that's in your abdomen than a tumors in your brain, for example. Just the sheer pressure in the brain will kill you.

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• 51:01Speaker 01

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• 51:30Sean Carroll?

  Is it is it something where different kinds of cancer are still going to need different kinds of T cells to come to life?

• 51:38Speaker 03

  Not necessarily different. They're all they're basically the same, same kind of T cell. So it's commonality, but it's those myeloid cells again that get in there because they can interfere in different ways. So we could, we got to work on those. But anyway, there's this other molecule called C2A4, which we just which we showed in the early 90s again was a break. So at the end of that expansion phase, that C 4 molecule starts coming up and stops the T cells from dividing. They've got to stop or they'll kill you.

• 52:11Sean Carroll?

  Yeah.

• 52:12Speaker 03

  Because they just, you know, they got to stop. You know, I mean, it's not, they don't become a cancer or something like that, but they'll just grow normally and use up all your nutrients and nothing left for everybody else. So you've got to stop that process. And that's what this molecule called C 4 does. And so the thing that we figured out in the early nineties was if you block that molecule, you can let the T cells keep going a little bit longer than they would normally, long enough to take out a tumor and then you stop the therapy and everything comes back to normal. And so that works spectacularly well in some kinds of cancer, just taking the brakes off for a while.

• 52:53Sean Carroll?

  Right. I mean, I know that one of the most terrible things you can hear when you have cancer is that it has spread, right? It's spread around the body. So it sounds like maybe this kind of therapy will be more amenable to even dealing with that.

• 53:09Speaker 03

  Yeah. Melanoma kills you because it, you know, ends up in the liver or the bone or the brain. Jimmy Carter had a melanoma in his brain. He got immunotherapy, it was cured, lived to be 100 and whatever, 100.

• 53:25Sean Carroll?

  Oh, okay.

• 53:26Speaker 03

  He was cured about seven years ago with immunotherapy of brain cancer.

• 53:31Sean Carroll?

  So I guess that that answers my next question, like, how much is this in the clinic now? Is there a pill that you can take? Is this growing?

• 53:38Speaker 03

  Yeah. No, it's not. No, it's all over the world. There are millions of people, literally, that have been treated. In fact, in melanoma now, immunotherapy is pretty much the standard of care is the first thing you'll get because it's so effective. The drug that we developed in the, in the late nineties, ipilimumab, that was approved by the FDA in 2011, that's given all over the world. As I said, millions of people have been treated and, and it cures overall by itself about 20% of people with metastatic melanoma. To put this in context, melanoma was Was one of the earliest targets for several reasons, but one of which is no other drug,

• 54:20Speaker 03

  no drug had ever had any effect at all in melanoma, ever. And so when you go over the immunotherapy, and also there are some indications that maybe it was immunogenic because there's a lot of mutations, but in any event, in our, with our drug, 20% of people are cured by one or two injections of an antibody. The therapy, by the way, is you sit in a chair for about an hour and they run a, you know, there's a drip bottle with a drug in it, and it's infused in your blood and you go home, and that's it.

• 54:53Sean Carroll?

  And that's better than chemotherapy as we know it.

• 54:56Speaker 03

  Yeah, and with luck, most patients, there's, you know, there's some scratchiness, there's some diarrhea, there's some, some stuff, but usually nothing really better. Occasionally, there can be bad stuff. Even, you know, patients, some patients get type 1 diabetes, which is all immune conditions. And maybe they already had it, borderline, and didn't know it, it just makes it worse. But, I mean, there's a downside, a lot of patients, but most stuff, it's not. Anyway, it was 20%, but then after we, after we started, our stuff started coming out, Tosco Hanjo in Japan, plus Arlene Sharp and, and Gordon Freeman at the Dana Farber discovered

• 55:41Speaker 03

  this other checkpoint. C24 was the first checkpoint, defined as a cell intrinsic, a molecule on the surface of a T cell itself that helps give a negative signal.

• 55:53Sean Carroll?

  Okay.

• 55:54Speaker 03

  So the T cell receptor obviously is a positive signal, it's the dishard switch. CD28 is the gas pellet, it's another positive signal. C24 says, stop all that stuff.

• 56:06Speaker 03

  It's time to quit. And so that's the one we chose to focus on was, you know, you can either make the other ones better. We chose, let's just take the brakes off, let's disable the brakes. And it worked spectacularly well, as I said, as a phase one trial. You know, which normally is just safety, you make sure you're not killing anybody and then saturate it up until they start getting really sick and then back off a little bit. And, and that's the way that cancer therapy used to be. So there you prove it's safety. You find the maximum tolerated dose. You know, how far can you go before you make people sick? And then you give that dose. And you give it until all the tumor is gone. And if the tumor grows at all, it's a failure.

• 56:49Speaker 03

  All of that's out the window with immunotherapies. First of all, there is no maximum tolerated dose usually. People either, I mean, they may have adverse events, but you know, you go up and up and you know, you might get, it gets more frequent in the population, but people don't necessarily get sicker. It's not like there's a poison, poisonous level of it. Uh, and with, in melanoma, in the first 14 patients, phase one, there were three whose tumors completely went away. You know, which was just unheard of at the time, particularly in melanoma. Cause in 2011, when the phase one, phase three trial, sorry, that, that I was associated with,

• 57:33Speaker 03

  uh, was unblinded and reported to the FDA. Uh, at that time, if you were diagnosed with metastatic melanoma, the median survival, 50% of people would be dead in seven months. Fewer than 3% would be alive at five years. After that, it was miniscule. It's not to say that everybody always died, but it was much less than 1%. Yeah. Would survive. Now, with just this one drug, 20% are alive at.

• 58:06Speaker 03

  Ten years plus. You know, with no other therapy, just one, one round of therapy, you're done. When Tosca came along with this other molecule called PD-1, which is a works a slightly different way, but the overall picture is similar enough. It's another checkpoint that works differently. If you put them together, there was just a trial that was just reported about a month ago. There was over a thousand people randomized, ten different countries. I don't know how many different PIs. I mean, the gold standard of clinical trials, ten years follow up. Fifty-five percent of the patients were still alive.

• 58:46Sean Carroll?

  Wow.

• 58:48Speaker 03

  So now we went from a, from a cancer, which was almost uniformly fatal in less than five years to we could cure more than fifty percent of the people with that.

• 59:01Sean Carroll?

  That is amazing, but so my immediate reaction is that twenty percent, fifty, fifty-five percent numbers are on the one hand, super impressive. On the other hand, why not a hundred percent? What have we got to do?

• 59:14Speaker 03

  Exactly. And that's exactly what we're working on now is how do we get that to a hundred?

• 59:20Sean Carroll?

  Yeah.

• 59:20Speaker 03

  And unfortunately, I don't want to get into that, but I'm not sure that the drug, the drug companies seem to be happy with fifty-five percent or so.

• 59:28Sean Carroll?

  Yeah.

• 59:29Speaker 03

  Anyway, it gets harder now, but, but, but that is the question, right? I mean, to me, that's, that's why we have this thing called, we have this institute that's been founded in Anderson and its whole goal is how do we make that better? And the way you make that better again is by bringing the myeloid cells in there. What are the ways, what are the things that are really, now we know, for example, there are a lot more of these things called checkpoints.

• 59:57Speaker 03

  Probably, I mean, there's a small number, it's probably a dozen, maybe. I don't know for sure, but did it influence the immune system in various ways that they regulate it? And some of them only pop up when you take one off. In some one sense, it's whack a mole, you know, you take one off and another one, because the immune system tries to regulate itself. The biology is just wonderful, just wonderfully complicated and the way it all fits together to make sure that everything that can happen, there's a counterweight to it. Multiple ways are built in. But, because it doesn't want to kill you. I mean, there are more, there are more ways of turning an immune response off than there are turning it on.

• 1:00:41Speaker 03

  Simply because the consequences of having it work when it shouldn't are too devastating, particularly if it kills you when you're young, you know? So it's all tuned to do that. But anyway, so one of the cardinal rules in performing drug development is make sure something has a single agent activity before you combine it with something else. That paradigm is shot here because some of those molecules aren't even expressed until you give one of the other ones. And so we've got to get off of that, you know, off of that sort of thing and understand it mechanistically. And so that's, I mean, what we're doing is going into humans as soon as we can, as soon

• 1:01:26Speaker 03

  as we know it's safe, and giving combinations to get biopsies and seeing what happened, what new molecules came out. Because now we can measure the advances that have been made in biology in terms of being able to do single cell transcriptomics and, you know, knowing every gene that's expressed essentially, and every protein that's made allows us to really understand what's going on. So if we can get biopsies after treatment, we can begin to unravel all this stuff. So that's what we're doing now is we try to work stuff out in mice, get a good idea it works, and then as soon as we can, with the help of Pam Sharma, who runs our clinical thing, go into patients, do a 12 picture trial.

• 1:02:10Speaker 03

  Safety and mechanism, not necessarily looking for an anti-tumor effect yet. But just, did we at least not hurt the patient and did we learn something about the mechanism? Maybe Vista is the name of another one of these checkpoints. Maybe Vista plays a role. Maybe the next time we need to add Vista to the cocktail. You know, so we go back, we add Vista then. See if that works, you know, so that's the idea is do this iterative thing. That's how we get it from 55% to 100%.

• 1:02:43Sean Carroll?

  And do I get, my impression is, or my guess would be that this kind of therapy might also have the benefit that can, you know, thinking of vaccines as, as an analogy, it sticks around in the body and it might help prevent what's coming next.

• 1:02:58Speaker 03

  Yeah, I mean, I think we, in a way, we do ourselves a bit of disservice by calling like the antibody that we made to C T L A four. It's the drug, it's not the drug. It's the thing that, it's the pro-drug, it's the T cell that's the drug.

• 1:03:13Sean Carroll?

  Right.

• 1:03:14Speaker 03

  And so that antibody is gone in a few weeks. The T cell is there for the rest of your life.

• 1:03:20Sean Carroll?

  Okay, so we're running to the end of the podcast, but so I'll ask one slightly crazier question. I mean, all these ideas about networks and switches and non-linearities. I'm a complexity scientist, among other things. It just makes me think of the study of complex systems. But i- is your work and the work of other people trying to do what you do, or is it just so focused on cancer and immunology that you don't have time?

• 1:03:47Speaker 03

  No, I think, no, that's, that's an excellent question, but I think that if we can learn how to resist, reverse this, we could treat autoimmunity. There's increasing evidence that a lot of neurodegenerative diseases involve dysfunctions in the immune system. We can really understand what we're doing. We might be able to do something about Alzheimer's down the road or, or Parkinson's or, or diseases like that. I mean, we're, we're thinking about that all the time. You know, and hoping that, you know, some of the data that we have will just people, I mean, it's the very simplest oversimplification is we just do the opposite of what we're doing now, maybe we can cure those diseases, you know, and, you know, so that, no, we, our

• 1:04:30Speaker 03

  institute is, our goal is to use the advances in basic science to advance medical practice. Right now, it's cancer. After we cure cancer, then we'll go after neurology.

• 1:04:43Sean Carroll?

  Never satisfied. Well, you know, one of the goals of the podcast is to give young, curious people, uh, food for thought about areas that are exciting and changing very rapidly right now. You've certainly done that for us.

• 1:04:56Speaker 03

  I think, you know, of course, I'm biased, but I think that it's a wonderful time to be doing this work. And it's become a systems biology problem more and more. And so single cell analytical techniques, uh, the ability to take a slide, you know, now to diagnose the cancer, you, you get a piece of the cancer, you stain it with hemotoxicin and heasen, you know, you get this purplish thing that you could look at shapes, the pathologist could say that's a cancer, that's not, there's some immune cells over there. Now we can look at that. And by doing some different analytical techniques, we could tell you every gene that's expressed in that cell. And what we already know is that the same cell that's

• 1:05:39Speaker 03

  here next to the cancer cell is going to be different than, than otherwise pretty much identical cell over here that's not in contact with the cancer cell. And the immune cell, the same thing, the immune cell that's next to the tumor cell is not going to be like the immune cell that's in the blood. And those, so now we can start to unravel one of those, one of those differences and how can we send the cells down, you know, we know that there are certain inhibitory molecules that the myeloid cells, particularly those that are in these complexes near the tumor cells express the terlates, those all, we can figure out how to just turn those molecules off. Myeloid cells, you know.

• 1:06:21Speaker 03

  Then, you know, but we got to know what they are first. I bring that up because I was just discussing with one of my postdocs, two molecules of that sort that we recently found that we're in the process of trying to do that with. But, but as the science, as the, the engineers and the computational people and all that are coming up with all these magical new things that I couldn't even dream of five years ago. I mean, that's how fast it moves. There's stuff we're doing now that I wouldn't even have guessed they would be doing five years ago. Uh, that it's, it's just such a fascinating time to be in biology. And I don't know, my motto is like, I mean, I've always been fascinated in science and biology.

• 1:07:06Speaker 03

  I think it's just as a, you might as well do something on there. Something helps people.

• 1:07:16Speaker 03

  Yeah. Cause you know, I mean, I like, I, I got into it initially because I just, you know, my family situation, but on the other hand, it's, it's fun and it's, it's rewarding and, and it helps people too. And so I think that, you know, it's a lot of it's drudgery too. Uh, but, but, uh, it's, you know, it's just puzzle solving. With the tools that we're getting that are coming, you know, from bioengineers and computational people are just allowing us to ask questions that we couldn't even have dreamed of.

• 1:07:55Sean Carroll?

  It's exciting times. Absolutely. Jim Allison, thanks so much for being in the Mindscape Podcast.

• 1:07:59Speaker 03

  By the way, I see you have a guitar. Do you play much or?

• 1:08:02Sean Carroll?

  Uh, that's a, that's a bass guitar that I'm very, very, very bad at. Uh, if, if we had more time or if you want to take another five minutes, I was going to say like, tell us the Willie Nelson story. Come on. It's so good.

• 1:08:14Speaker 03

  I'll tell you one funny one. I had a knee replacement.

• 1:08:20Speaker 03

  Last, uh, what was it? Last year? Yeah. Anyway, and really I'd play with him occasionally, but he, he, um, they asked me to come to Austin. I'm in Houston, you know, his Fourth of July pic pics in Austin. So I said, would you come down? I mean, he didn't, but his, his wife and his, his harmonica player is a friend of mine. So Jim, come down, join us. I said, I can't. I just had knee surgery and I don't want to go down there. And I said, well, we just happened that they were playing at this place called The Woodlands, which is just north of Houston, near this lake where I have a lake house. I was recuperating from the surgery there. They said, well, hell, we're going to be there on Saturday night.

• 1:09:00Speaker 03

  So why don't you come and play there? We, we, you know, I said, well, I can't walk very well. They said, well, get a wheelchair.

• 1:09:07Sean Carroll?

  Yeah.

• 1:09:07Speaker 03

  We're going to travel. So I said, okay, okay. So my son got a wheelchair. We got some friends. We went down, wheeled me in. I'm still on the edge of the stage. And so I was waiting to play, but I still wasn't sure I could go out there. And one song came by and, you know, they said, come out. And I said, no, I can't, I can't stand yet. I had a, I was in a wheelchair. I had a cane. Anyway, Willie got into the gospel. He always closes concerts with a gospel medley. I saw the light. Will the circle be broken? I'll fly away. You know, all the great old songs. Anyway, so that's so much fun to play. And, and, you know, he said, you know, Mickey, you know, waves me out there.

• 1:09:48Speaker 03

  They had a microphone for me. I just said, no, Willie's wife, I said, Allison, get your ass out. So anyway, so I jumped up and took a couple of steps before I, I didn't even think, you know, I just stood up. And I had a cane in one hand, a harmonica in the other. And then I realized this isn't gonna do because I need both hands when I get out there. So I turned and I threw my crane behind me. And then turned back around and took a couple of steps towards the mic and this woman screamed, he's healed. Willie healed him. Praise the Lord.

• 1:10:24Sean Carroll?

  Evidence.

• 1:10:26Sean Carroll?

  It was not a double blind study, but yeah, some data there.

• 1:10:29Speaker 03

  Willie starts and I saw the light, you know, it was just so perfect, you know.

• 1:10:34Sean Carroll?

  Congratulations on being the recipient of a miracle. It sounds like you deserved it there.

• 1:10:39Sean Carroll?

  All right, once again, Jim Allison, thanks very much for being on the Mindscape Podcast.

• 1:10:42Speaker 03

  Okay, bye bye. Thanks.

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