Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 303 | James P. Allison on Fighting Cancer with the Immune System

Episode Date: January 27, 2025

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. 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 at MD Anderson Cancer Center. He is the subject of the documentary film Jim Allison: Breakthrough. Among his numerous awards are the Breakthrough Prize in Life Sciences and the Nobel Prize in Physiology or Medicine. Web page Nobel Prize citation Google Scholar publications Wikipedia

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With 20 grams of collagen sourced from grass-fed, pasture-raised bovine, it helps support healthy hair, skin, nails, bones, and joints. Made with no artificial sweeteners, it's a lot. clean way to fuel your body. So your wellness stays effortless wherever the day takes you. Vital Proteins. Stay vital. Visit VitalProtene's.com to get started. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease. 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 going to 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 you have to worry about checking for it yourself, but you know people who have had cancer and even who have died because of it. 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 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, very complicated, very, very complex networks of reactions and cells and proteins and molecules and all of 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. James Allison, welcome to the Mindscape Podcast. Thank you. Glad to be here. 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? 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, if 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. I guess 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 and some therapies work better than others. Is it accurate to call it one thing? No, it's not. Well, it depends. I mean, the common thing is it cells growing 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. There are different tissues, first of all. That's where it used to be classified, solid, you know, in muscle or whatever, solid tissue versus leukemia's, 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. First, crudely, you know, carcin, obviously carcinogen-induced and obviously virus-induced or something.

Although viruses are a tiny fraction of it, it's not zero, but that's not the main thing. But the common thing is just mutation. And the functional classification according to causation can be useful. And for a while, it 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 tells the cell, well, you better divide because we need to cover up that scrape or that fix that cut 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. So this was all the excitement around nearly 2000s, 2010, up to about 2015 was. And most of these enzymes that do these things are tyrosine kinases or forms thereof. And so that is, you can 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. And you can 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 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 can take one out. It doesn't make any difference. You can 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.

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. Yeah, that's not totally universal, but generally it's true that the tumors become, as they progress, become less and less stable. and so the idea of having a magic bullet that can attack it at its source is really yeah 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 as an immunologist tend to look at things differently because the tumor biologists,

you have to take the classical tumor biology view of cancer would say, oh, well, you've got that mutation, let's attack it, and we'll be done so we should concentrate on what's going on there. On the other hand, so there's lots of mutations. The mutations really occur pretty much randomly. It's when they hit, you know, so they've got to hit. generally a couple of genes before you've got problems, a couple of very types of genes that are very specific.

But the other ones, the cat's biologists say, oh, well, those are irrelevant. They're passengers, or they're not important because they're not drivers. The immune system, on the other hand, you know, trains in immunologists, your immune system is just, its purpose is to find things that shouldn't be there. Exactly. They're what they do, you know.

that shouldn't be on my cells. 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 switch to the cancer biologists are not important because they're not the drivers. Yeah, okay. They're equally important to the immune system.

The immune system doesn't know the difference. It just does. There's something different here. We better get rid of that guy. You already mentioned that it's a little bit surprised. to you that the body lasts as long as it does and works as well as it does. I mean, 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. Well, evolutionarily, you know, it's all evolution. Unless it takes you out before you reproduce, evolution doesn't care.

You know, if you get cancer when you're 50, evolution doesn't care. Right. It doesn't matter about it. But some animal species, are pretty good at avoiding cancer. It does seem to be possible. Do we understand that? No.

No, I wish we did. No, I think. Maybe they have a really good immune system. I doubt it. 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? Yeah, now that's true. I guess elephants don't, 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. That's true. But mice, happily, we're able to give cancer to because that's where we do a lot of tests. Not so good for the mice.

So how much do we know about, I know this is not, 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? Well, there's some such an 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 if you get out of the sun a lot and expose your skin to ultraviolet radiation, and chances are you're going to get mutations in your skin that can cause melanoma because that's, you know, what the sunlight hits.

and, you know, if you stay out of the sun, you're probably not going to get melanoma, although plenty of people saving lung cancer, you smoke, you know, you're highly, you know, you're a lot more likely to get, but you're not, if you don't smoke, I mean, you're not going to get lung cancer. No. Because the cells divide, there's, there's, they're mistakes. 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, et cetera.

Let's go back historically. Let's go back way to the start. You know, there's evidence that the Greeks, you know, knew about tumors and they cut them off. Okay. And so the very first cancer therapy was surgery. Got it, yes. And that still is perhaps the most effective. If you can get it at 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 kind of big way it's already spread to other organs in your body prostate same way so 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 beginning of the 20th century um madam curie in particular uh developed radiation therapy and that was quite useful and curative in some cases. Of course, it also caused cancer, you know, if people learned by spionogenic effects, but the idea was you blast a cell and given enough mutations that it can't live. The problem, of course, is that it also kills the normal tissues. So you got to be careful about that. And then it's oddly enough,

with the advent of mustard gases and things during World War I and chemical warfare, ages that were developed leading into World War II, ultimately led to some pioneers in cancer therapy in the 50s, you know, applying it to leukemia's childhood leukemia's in particular, mustard, I mean, just toxic gases that, toxic chemicals that were used to mustard gas, for example. Those were the basis of the first chemotherapies. they kill dividing cells. Why are they good at killing cancer cells? They cause a lot more mutations, you know,

as they screw up the DNA as it's dividing and make it sure that the cell can't successfully divide without. Unfortunately, you could also put it in a lot of mutations that will make you more likely to get a cancer down the road to, you know. But they also, but the bottom line, With both of those, both radiotherapy and chemotherapy as given, unless you kill every last tumor cell with those techniques, those approaches to it, the tumor's going to win because it'll just come back.

And so you have to blast them so hard 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. 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 they're like my brother. And it's, it's, you know, it's a, it's a devastating thing. Not just the cancer, but the consequences of the therapies. On this episode of plant killers, we'll explore one nation's most notorious fruit and

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Indeed.com slash podcast. Terms and conditions apply. Need to hire? This is a job for Indeed sponsored jobs. And do tumors spread just because the cells in the tumor sort of get kids? carried around by the blood system? It's a little more complicated, but Matt, there are signals that tell them to stay where they are. Those could be lost, but they can also develop things on their service

that'll tell them where you really belong over here, you know. Okay. So it'll leave. I mean, that's the way they get there is 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 other area of tachesis of study that's underwriting. And my understanding is that you started as a chemist, an actual chemist, more than a sort of biologist or medical person. Yeah. Well, a biochemist. I got bored with chemistry, we're in 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, I was lucky enough to have an immunology course as an undergraduate at University of Texas at Austin. And Bill Manney, the professor, towards the end of the – 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. Screen your cells and see what's going on. Every of the remotest corner of your body is being surveyed, surveilled, I guess the proper verb 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. One of the reasons early on. First of all, most of the mechanisms for replicating are pretty damned accurate. But if they're accurate, 99.9% of the time, that's not enough.

Not enough. You're going to get problems. And T cells are there a variety of white blood cells? Yeah, yeah, a variety of them. Yeah, bs. 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. Miloid 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. And they have innate signals that are called that they can recognize a lot of viruses

and a lot of bacterial just because they have carbohydrates and things on their service that is classes of molecules are different than those found in our cells, mammal mammalian cells. So they're sort of this, we call it me 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 anyway, evolutionarily, this other system came on, which we call the adaptive immune system, where you actually have receptors that are made by random recombination of DNA sequences. I don't want to go to 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 every receptor that can be made with the structures that are in there. It's really a fascinating area of biology in its own,

but it's 10 to the 15th, maybe 10 to the 17th power. Yeah. You only have about 10 to the 10th cells in the 12th cells. 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 the population is protected probably, but not the individual necessarily. Well, I was going to ask, do the T-cells in our body develop new receptors?

Do they learn on the job? or does the body make new? No, they're generated essentially randomly. Okay. The 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 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 8 to 10 amino acids, 8 to 12 maybe amino acids long, that are presented in the surface of this thing. It looks like a hot dog bun. It's got a peptide in the middle of it. There's a peptide

for virtually every protein that's made in your body that'll bind there and 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 they normally wouldn't be on the cell surface. If it's a virus that's just infected a cell and the cell starts making bits of virus, 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 it says, whoops, that shouldn't be there.

They don't kill it. It's essentially random. So the cell is sort of doing its own annual checkup at all times. Exactly. But you've got to get rid. A lot of those are going to be harmful. They may be harmful. And so they got to, 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. So you end up with, you know, different autoimmune syndromes and stuff. Sorry, these are T cells that can be dangerous if they're not in the right kind? Yeah, if there's auto-reactive, they react with self-protein. Or sometimes if a virus comes in and tricks the immune system into thinking something's foreign, when it's closely enough to a cell thing, get occasionally you'll get a spillover,

can be damaged, like for measles and stuff, you know, down the road. But anyway, basically, they're pretty damn good, though. 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. Yeah, how many stars are there? Well, there's a lot of stars, but stars are pretty similar to each other.

There's 10 and the 22 stars out there, but, you know, they're not that different. There's no locking key in there. I mean, I guess that's my question. Your talk about receptors reminds me of people who are trying to study smell and how we're sensitive to different kinds of molecules.

Is it a similar kind of thing going on? Yeah, in a way, except that there, what you have is one kind of receptor for each kind of bit of a smell. And as the sum of all those that tells you what the overall smell is. But each one only detects one and the brain integrates it all.

Yeah. Because here you've got all these different ones that are flowing all around. All you need to do is trigger one. And so the job of a T-cell is to understand what the normal healthy cells are like and target anything that is not that. Exactly. Not self-recognition is what it's called. Philosophically, a very, how do you recognize not-self?

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. Yeah, that's first of all because cancer cells are not necessarily all that different early on, especially, although they get weirder and weirder and with time 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 are mechanisms that guard. The 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.

At least that's 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. In order to get it. That's right.

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 germline, 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 support. That helps because I did have the question, you know,

do tumors or do cancer cells defend themselves? You know, 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. 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 ever 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. They think the wound. So your own immune system can turn around.

And we're finding that that's one of the reasons. That happens big time in pancreatic cancer and in glialostoma, you know, which are tumors that are very lethal. And 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 functions to protect tissue and help it heal. They just happen to, you know, they get in a weird 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 could also help the T cells. It just depends on what they're doing. It's a whole new area of biology 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 they're about seven kinds. The truth is that those kinds are just constructs that we make up. And biology, it's a continuity. You know, it's just a continual spread. In myloid cells, it's really pronounced. You can see all these different cells. They differ by two or three genes that are being expressed. And you can just shift the population one way or another,

and that's what we're trying to figure out. And shift them from this protective overall effect to the helping, you know, to help the immune system rather than hinder it. What impression I get from reading about these are 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. Yeah, 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. how much you know it sounds like with the receptor stuff on the 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're in like 1980s or whenever it was like is the technology changed things well yeah I mean in the 70s nobody knew what the T-cell receptor

was. I mean, that was my first thing when I got into immunology was, what is the antigen receptor? What is it that the T-cell uses? So 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 published that for the first time. I mean, 82, it's going to look like this. And I had data and stuff. And then the genes were cloned a couple years later and confirmed that that's 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 outside it gives you the combining site but how is it presented and so there was this i don't go to the details too much but that's another complicated thing how the molecule that hot

dog it doesn't you know every weener won't fit of that bun, you know, everybody, bun's a little bit different, holds a different kind of wiener. And so, you know, if you've got the right, you know, bun for the peptide, you can 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 going to see it. We don't mind a little bit of details here. You're allowed, like, if you really want to go into details, we'll go with you a little way. Okay, well, I won't go anymore, but it's, But it's a complicated thing.

But we didn't know this stuff until the 80s and the 90s, and now we're beginning to understand in some detail. And now with a lot of the work in terms of really understanding the biology of it, some of this new work from the Nobel Prize this year, David Baker, for example, and understanding how sequence and forms shapes. how shapes influence, sequence cells, we're beginning to understand at the molecular level

or how these interactions occur and how to manipulate them a little bit better in ways that we couldn't even think about 10 years ago, much less in the 80s. Need skills for the job market now? Santa Monica College offers career programs you can complete in as little as one to four semesters. Get job ready with flexible classes and real-world training

and roll for summer at SMC.edu. 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. Yeah, I'm one of these old school guys that thinks hypotheses are useful. Yeah. Now it's get a whole bunch of data and try to pull something out of it, you know. 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? Yeah, pretty much. Those are the things that have 10 to 70 different possibilities. That's really helping with vaccine design 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 HPV-induced cervical cancer and head-in-neck cancer. by the HPV vaccine if it was people would just use it.

They're more importantly in the clinical realm or 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. This was something was greatly informed by the, by the, our recent epidemic, you know, with the virus, with the vaccine strategies that were developed

then, 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 going to, we're going to, I think we're going to come up, there's going to be eventually a small set. of adapters, you know, you can use. It'll have all the signals that you need to properly activate the innate immune system and all that. But you put your specific thing in the middle of it, and we can generate a vaccine in weeks.

Pretty good. I mean, is this part of the sort of CRISPR revolution of gene editing? That's part of it. Yeah. It's part of it being able to get the genes out. It's more useful right now in testing as to whether you're right by actually doing fine structure and seeing if you can initiate or terminate an immune response by, you know, manipulating things. But yeah, it's that and just all the work that went in developing about the coronavirus

vaccines, the COVID vaccines. But that's sort of framework. It's not exactly the same thing, but there's 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 that'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 which ones will be presented and then you can just have the proper vaccine to snap it into that thing and start vaccinating people. So 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, what is it, Lynch syndrome. They get a lot of polyps, you know, I mean, virtually go on and develop colon cancer. It's definitely a 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, and women with breast cancer and over-hane 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,

individually specific to you that there's no way you're going to have a vaccine you can prophylactly treat the population for most cancers you're going to have to come up with something really powerful and I was going to jump start a response as soon as you detected and I think we're getting close we're not there yet but I was actually going to ask about the role of simulations I mean as a in physics in 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 two individuals, so we have to actually test the pharmaceutical in a living thing rather than just putting it on a computer.

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. So, okay, so we have this. 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? Yeah, well, again, it's because one of them is big, and it's largely they're individual. So your tumor has mutations that nobody else has has. So you've got to tailor it to the individual. And secondly, there are ways that the tumor can lose.

For example, the peptide has to be from the containing the mutation has to get on the cell 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. the immune system can't see it because it doesn't get to the service of the cell. There are ways around that that we've got to have them.

But that's what happens and has been shown in melanoma, for example, patients. Just quit making the molecule that carries it. But there are other ways around that we're beginning to come up with. But that's one easy mechanism. Another one is that one of the main ways that tumors kill tumor cells is by making gamma which is a cytokine that I mean you've heard of but one of its activities besides helping protect your 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 gamethorae

the thing that detects gametiferoon and tells the cell it's around if you mutate anything in that pathway then that doesn't work anymore either and so the T cells can make all the gamethora matter for a minute they won't, the tumor won't, you know, will respond to it. So there's that too. So what is our goal as immunotherapists? Are we trying to teach the T cells to ignore some of these problems? Well, first is just to get the T cells. Yeah.

That's the, and then secondly, in 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 cells. we're only beginning there. But ultimately, how do we deal with these things that comes down? So it's not that you could get the T cells to do any better, but you can 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, though 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, put it on their surface. If they have the antigen and a T-cell sees it there and they can make enough of these gameteer phrains or other things, then they can kill the tumor cells at a distance, even though they don't interact physically directly with the tumor cell anymore. I mean, we can show that happens in animal models,

at least I'm pretty sure it happens in people as well. 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. Yeah, well, the reason, I mean, I used to avoid the things like a plague because they're so complicated, there's so many different types. But what we started, 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 myloid cells in them. So that raised the interest. And sure enough, you can show that the myeloid cells can inhibit T cells. And 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 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.

What are the myeloid cells? What's their role when everything is going well? Gobble up bacteria that come in. Deal with if antibodies, if you've made antibodies and they're binding to viruses or bacteria and clumping them up to gobble up and get rid of the bugs that way. As I said, to wound heals, to help wounds heal. Okay, good.

Make growth factors and stuff, you know, just sort of generally handymen. they're just sort of general handymen that do whatever fixer-uppers or you need but they can get in the way and they have this spin-off effect that they can basically communicate the existence of a tumor to the T-cells if you're triggered them right yeah or they can hide them from the tumor cells too they can hide the tumor cell from the T-cells too right if things are going badly and isn't there also this is my very vague understanding popping up, but you can get in trouble if you make too many T cells. Yeah. If you make too many T cells, you can definitely get sick. And especially if they

react with normal cells or something that makes a big soluble factors that affect. And that unfortunately is one of the main side effects of the therapies is cross-reactivity with normal tissues of things. 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.

Oh, wow. You know, other people are getting very sick. And sometimes there can be things which can be fatal. Thank God 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, I've still got time. 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? 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 C2A4 in the 90s. You know, there was this molecule. It was funny. It looked like a molecule that was the gas pedal of T cells.

But this molecule called C2A4, and we showed that it was actually not a gas pedal. It was a break. And 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 earlier in the 80s.

Show that CD28's another molecule. It's like the gas pedal. So the antigen receptor you can 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 like the gas pedal. And that's a molecule called CD-20A that we showed.

in the late 80s, you know, was the gas pedal. If you don't push on that, activating through the antigen receptor doesn't do any good at all. T cells don't do anything. Tumers never have, on their 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. tumor, and we worked this out in the early 90s, the tumor gets big enough or whatever, causes inflammation. The innate immune system comes in. The innate immune system has those things that they're called B7 for, they can be called Frank. It doesn't matter. I mean, it's just the name means nothing, but they buy the CD28 and that says go. So the only way that the immune system with solid tumors, and this is that we published this in the early 90s,

was 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 ninth, different, nobody really knows for sure, but different T cells in your body with different receptor. 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 a hundred dense. And so you have to expand. And so that's what this. So the T-Soreceptor Act sees the ignition switch. And then when you, but nothing happens really until you push on the CD28 molecule of gas pell. Then they take off. You've got to generate 100,000.

I mean, you've got hundreds of thousands to millions of cells to swarm through the body and look for things. I mean, what's so cool about because then you don't need to know where to cut or know where to shine the radiation or whatever. You'd have the T cells go find it. Go find the micrometastases, you know, the little clumps of tumor cell under your toenail or wherever. I mean, that's an exaggeration. But anyway, they go find the tumor cells wherever they are. take them out or at least keep them in control where they don't grow anymore. But that process has to happen fast or the tumor wins.

And so tumors are going to go very fast generally, yeah? Right. And see, well, not that fast. It takes years generally. It's at the end when they start damage. Oh, okay. But 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 of, lot more degrees of freedom than a tumor that's in your abdomen than a tumor's in your brain, for example. Just the sheer pressure in the brain will kill you. Pasadena Playhouse presents learner and Lois Brigadune, featuring six-time Emmy Award winner Tyn Daily and a full 21-piece orchestra. With its a lush score, including Broadway standards like

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looks like Bad Dirt's murdering days are over. Thanks to Miracle Grow. Join us next time on plant killers. Is it something where different kinds of cancer are still going to need different kinds of T cells to come to life? Not quite different. They're basically the same kind of teeth.

So there's commonality, but it's those myeloid cells again. They get in there because they, can interfere in different ways so we can we got to work on those but anyway there's this other molecule called c till a four which we just which we showed in the early 90s again was a break so at the end of that expansion phase that c2a4 molecule starts coming up and stops the T cells from dividing they've got to stop or they'll kill you yeah because they just you know they got to stop you know i mean it's not they don't become a cancer i mean it's not they don't become a cancer i mean it's

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's 4 does. And so the thing that we figured out in early 90s 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 the 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. 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. Yeah. Melanoma kills you because it, you know, ends up in the liver or the bone. of the brain. Jimmy Carter had a melanoma in his brain. He got immunotherapy.

It was cured. There to be 100 and whatever, 100. Oh, okay. He was cured about seven years ago with immunotherapy of brain cancer. So I guess 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?

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, Aminotherapy is pretty much the standard of care. It's the first thing you'll get because it's so effective. The drug that we developed in the late 90s, epilumab 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 it cures overall by itself about 20% of people with metastatic melanoma. To put this in context, melanoma was, was. was one of the earliest targets for several reasons, but one of which is no other drug, no drug had ever had any effect at all in melanoma, ever. And so when you go to immunotherapy,

and also there's some indications that maybe it was immunogenic because there's a lot of mutations. But in any event, 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 there's a drip bottle with a drug in it. It's infused in your blood and you go home and that's it. And that's better than chemotherapy as we know it.

Yeah. And with luck, most patients, there's, you know, there's some scratchiness, there's some diarrhea, there's some stuff, but usually nothing really better. Occasionally there can be bad stuff. Even, you know, patients, some patients get type 1 diabetes, which are an immune condition. Maybe they already had it, borderline, I didn't know it. It just makes it worse. But, I mean, there's a downside, a lot of patients, but most of the time it's not.

Anyway, it was 20%, but then after we started, our stuff started coming out, Tasco Honjo in Japan, plus Arlene Sharp and Gordon Freeman at the Dana-Fourber, discovered this other checkpoint C2A4 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 okay so the T cell receptor obviously is a positive signal it's the district switch CD28's the gas pellets another positive signal C2A4 says stop all that stuff 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 works spectacular 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 not trade 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 safety you find the maximum tolerated dose, you know, how far can you go before you make people sick? I mean, you give that dose and you give it until all the tumor's gone. If the tumor grows at all, it's a failure. 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, 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. And 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, because in 2011, when the phase one, phase three trial, sorry, that I was associated was unblinded and reported to the FDA. 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 minuscule. It's not to say that everybody always died, but it was much less than 1%. Yeah. It would survive. Now, with just this one, one drug, 20% are alive at 10 years plus. You know, with no other therapy, just one, one round of therapy, you're done.

When Tosco came along with this other molecule called PD1, which works a slightly different way, but the overall pictures, 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 10 different countries. I don't know how many different PIs. I mean, the gold standard of clinical trials, 10 years follow up, 55% of the patients were still alive. Wow.

So now we went from a cancer, which was almost uniformly fatal in less than five years, to we can cure more than 50% of the people with that. That is amazing. But so my immediate reaction is that 20% 50, 55% numbers are on the one hand, super impressive. On the other hand, why not 100%? What do we got to do? Exactly. And that's exactly what we're working on now is how do we get that to 100?

Yeah. And unfortunately, I don't want to get in a little, but I'm not sure that the drug company seem to be happy with 55% or so. Anyway, it gets harder now. But that is the question, right? I mean, to me, 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 you? Now we know, for example, there are a lot more of these things called checkpoints. probably, I mean, there's a small number. It's probably a dozen, maybe. I don't know for sure, but that influenced the immune system in various ways that they regulate it. And some of them only pop up when you take one off.

In 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 of built in. But because it doesn't want to kill you. I mean, there are more ways of turning an immune response

off than there are turning it on. Simply because the consequences of having it work when it shouldn't are too devastating, particularly if it kills you when you're young. 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. It's 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. And so that's what we're doing now is we try to work stuff out in my skin, a good idea it works,

and then as soon as we can, with the help of Pab Sharma, who runs our clinical thing, going to patients, do a 12-patient trial. Safety and mechanism, not necessarily looking for an antitumor 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 and 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 for 55% to 100% and do I get my impression is or my guess

guess would be that this kind of therapy might also have the benefit that can, you know, thinking of vaccines as an analogy, it sticks around in the body and might help prevent what's coming next. Yeah, I mean, I think we, in a way, we do ourselves a bit of disservice by colleague, like the antibody that we made to C2A4. It's the drug. It's not the drug. It's the thing that, it's the pro-drug. It's the T-cell. It's the drug. Right. And so that antibody, everybody's gone in a few weeks. T-cell's there for the rest of your life. 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 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 to... No, I think... No, that's an excellent question, but I think that if we can learn how to reverse this, we could treat autoimmunity. There's increasing evidence that a lot of neurodeginative 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 Parkinson's or diseases like that. I mean, we're thinking about that all the time, you know, and hoping that some of the data that we have will just people, I mean, it's the very simplest oversimplications. We can just do the opposite of what we're doing now. Maybe we can cure those diseases, you know. And so that, no, we, our 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 neurological. never satisfied well you know one of the goals of the podcast is to give young curious people food for thought about areas that are exciting and changing very rapidly right now you've certainly done that for us 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-cellar analytical techniques, the ability to take a slide.

You know, now to diagnose the cancer, you get a piece of the cancer and you state it with hematoxidone, and 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 can tell you every gene that's expressed in that cell.

And what we already know is, that the same cell that's here next to the cancer cell is going to be different 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 so now we can start to unravel. What are those differences and how can we send the cells down there?

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 to turn the T cells off. We can figure out how to just turn those molecules off in the myeloid cells, you know, then, you know, but we got to know what they are first. I'd bring that up because I was just discussing with one of my postdocs, two molecules of that sort that we recently found that were in the process to try to do that. with, but as the science is 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 wouldn't even have guessed it would be doing five years ago. That it's just such a fascinating time to be in biology. And I don't know, my motto is a, I mean, I've always been fascinated in science. that's involved. I think it's just as a, you might as well do something on the area

of something helps people. Because, you know, I mean, I got into it initially because I just, you know, my family situation. On the other hand, it's, it's fun. And it's, it's rewarding and it helps people too. And so I think that, you know, a lot of it's drudgery too.

But it's just puzzle solving with the tools that we're getting that are coming from bioengineers and computational people are just allowing us to ask questions that we couldn't even dream. It's exciting times. Absolutely. Jim Allison, thanks so much for being in the Mindscape podcast. By the way, I see you have a guitar. Do you play much? That's a bass guitar that I'm very, very, very bad. at 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 I'll tell you one funny one I had a knee replacement last uh was it last year yeah anyway and really I'd play with him occasionally but he asked me to come to Austin I'm in Houston his fourth of July picnics in Austin So I said, would you come down? I mean, he didn't, but his wife and his harmonica players, a friend of mine. So Jim, come down and join us. I said, I can't. I just had knee surgery.

And I don't want to go down then. They 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 lakehouse. I was recuperating from the surgery there. They said, well, hell, we're going to be there on Saturday night. So why don't you come and play there? I said, well, I can't walk very well. They said, well, get a wheelchair.

Yeah. He drove up to travel, so I said, okay, okay. So my son got a wheelchair. We got some friends. We went down, wheeled me in, and 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 was in a wheelchair, I had a cane. Anyway, Willie got into the gospel. He always closes. with a gospel medley. I saw the light. Will the circle be broke? I'll fly away, you know, all the great old songs.

Anyway, so that's so much fun to play. And, you know, he said, you know, Mickey, you know, waves me out there. He had a microphone for me. I just said, no. Really's wife got by her. He 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 had a pain in one hand, a harmonica and the other. And then I realized, this isn't going to 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. It took a couple of steps towards the mic and this woman screamed, he's healed. Really yielded him.

Praise the Lord. Evidence. It was not a double-blind study. It really starts into, I saw the light. You know, it was just so perfect. Perfect. Congratulations. I mean the recipient of a miracle.

It sounds like you deserved it there. All right. Once again, Jim Allison, thanks very much for being on the Minescape podcast. Okay. Bye-bye. Thanks.