James P. Allison
Appearances
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
with those techniques, those approaches to it, the tumor's gonna 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, and you're sick.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And that's what I saw when I was growing up, and my mother and two of her brothers, and my brother, And it's a devastating thing, not just the cancer, but the consequences of the therapies.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
There are There are signals that tell them to stay where they are. Those can be lost, but they can also develop things on their surface that'll tell them where you really belong over here. So it'll leave. I mean, that's the way they get there is through the blood, but it's more complicated.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. That's a whole other area, metastasis of study that's under way.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah. Well, a biochemist. I got bored with chemistry and biochemistry quickly. Actually, then when I was – but again, I had this family history of cancer, which made me –
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
was interested ultimately i was interested in biology um 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 um i was really fascinated by the whole idea of the immune system and but it was mostly antibodies and b cells at the time but then when t cells came along
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I was lucky enough to have an immunology course as an undergraduate at University of Texas at Austin. And Bill Manny, the professor, 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 they go all through your body.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 surveilled, I guess the proper verb, by the immune system to make sure nothing's going awry. That's one of the reasons we're able to keep it all together without going completely bananas.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
You're going to get problems. And T-cells are, they're a variety of white blood cells? Yeah, yeah, a variety of them. Yeah, 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
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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, they're called, that they can recognize A lot of viruses, a lot of bacteria, just because they have carbohydrates and things on their surface that is classes of molecules are different than those found in our cells, mammalian cells.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
So there's 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 after vertebrates and things.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But anyway, evolutionarily, this other system came along, 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 into the details, but basically essentially random processes that give you a random set of different receptors. It's been calculated...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 and 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, 10 to the 12th cells.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 realized only a fraction of the possible diversity of different T cell receptors that could be made. in your body, to the species. So the population is protected, probably, but not the individual, necessarily.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And there's this fascinating testing system where there's a scaffold on cells that presents the antigens, which are little bits of protein. There 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
There's a peptide for virtually every protein that's made in your body. It'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 the thing normally wouldn't be on the cell surface.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 go out and infect 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 if the right T cell comes by and says, whoops, that shouldn't be there, it'll kill it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
It's essentially random.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Exactly. But you got to get rid. A lot of those are going to be harmful. They may be harmful. And so they got 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...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
know different autoimmune syndromes and stuff that's right sorry these are t cells that can be dangerous if they're not in the right kind yeah if they're autoreactive 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 self thing occasionally you'll get a spillover uh can be damaged uh like for measles and stuff
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
you know, down the road, but, but anyway, basically they're pretty damn good though. Yeah.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah. How many stars are there?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, in a way, except that there, what you have is one kind of receptor for each kind of 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. Because here you've got all these different ones that are flowing all around. All you need to do is trigger one.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Exactly. Not self-recognition, that's what it's called. Very philosophically, a very, how do you recognize not self?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
You know, 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 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 cause cancer. At least that's the thought. But there are these suppressor genes which do that.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 got to get rid of those suppressor genes which would shut that down so it's genetically it's complicated too because you really have to have both um in order to get it that's right some people with retinoblastoma gene for example
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. They think the tumor is a wound. And so your own immune system can turn around.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And we're finding that that's a re one of the reasons that happens big time in, in pancreatic cancer and, and, um, um, glioblastoma, 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 them.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 situation where they are treating the tumor like a wound and protecting it from the immune system.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with 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
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
that single-cell RNA techniques and things are making us realize that when 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. In biology, it's a continuity. It's just a continual spread.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
In myeloid 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 then shift them from this protective overall effect to the helping one. a thing to help the immune system rather than hinder it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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? 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 published that for the first time in 82.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
it's going to 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 what it was, an alpha chain, a beta chain, two chains of protein, both of which have constant regions and then variable regions. That's how they give you the combining site. But how is it presented? And so there was this
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 wiener won't fit into that bun. You know, everybody's bun's a little bit different. It 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Okay, well, I won't go anymore, 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...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
The new work from the Nobel Prize this year, David Baker, for example, in understanding how sequence informs shapes and how shapes influence sequence. All this we're beginning to understand at the molecular level, 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 80s.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, I'm one of those 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, pretty much. Those are the things that have 10 to 17 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...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
develop prophylactic vaccines i think certainly for hpv we're there we can prevent we can prevent hpv induced cervical cancer and and and head and neck cancer by the hpv vaccine if it was people would just use it um they're more importantly in the clinical realm or therapeutic vaccines now and we understand we're beginning to understand enough about
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
the antigens that are induced by the mutations where we can begin to come up. This was something that was greatly informed by our recent epidemic 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 think there's going to be eventually a small set of adapters you can use.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
That's part of it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
That'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 manipulating things. Okay. But yeah, it's that and just all the work that went in developing about the coronavirus vaccines, the COVID vaccines.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But that sort of framework, it's not exactly the same thing, it's going to 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 people's, it's called MHC type, the genes that you have that influence what you present.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 design 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 Oh, what is it? Lynch syndrome.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
They get a lot of polyps, you know. They eventually 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
BRCA mutations are associated 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 individually specific to you that there's no way you're going to have a vaccine. You can prophylactically treat the population.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
For most cancers, you're going to 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah. Well, again, it's because one of them is big and largely they're individual. So your tumor has mutations that nobody else has had. So you 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 containing the mutation has to get on the cell surface by these MHC molecules.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And if you lose expression of MHC molecules, then they're invisible to the immune system. The tumor will still be there. The mutation will still be being made, but the immune system can't see it because it doesn't get to the surface of the cell. There are ways around that that we've got to have them, but that's what happens.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
It's been shown in melanoma, for example, patients just quit making the molecule that carries it. But there are other ways around that 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 interferon.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
which is a cytokine that, I mean, you've heard of, but one of its activities, besides helping protect you against viruses, it 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,
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
If you mutate anything in that pathway, then that doesn't work anymore either. And so the T cells can make all the gamma interferon they want, and the tumor won't. respond to it. So there's that too.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Well, first it's just to get the T cells. And then secondly, in importance, is do something about the myeloid cells, which were not there yet. We're getting close on the T cells. The myeloid cells, we're only beginning there. But ultimately, it's how do we deal with these things that comes down.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. It's kind of hard to explain, but a different type of T cell, like more soluble factors, maybe see the antigen on a myeloid cell, even though the tumors can't present it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 gamma interferons 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I mean, we can show that happens in animal models, at least. I'm pretty sure it happens in people as well, but.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, that's 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 found 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 myeloid cells in them.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 us to some more strategies where you target the myeloid cells.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But you're going to have to do both, particularly in things like pancreatic and glioblastoma.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Gobble up bacteria that come in. 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 and get rid of the bugs that way. As I said, to wound heal, to help wounds heal, to make growth factors and stuff, you know, just sort of general handymen. They're just sort of general handymen that do.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
whatever fixer-uppers you need that they can get in the way.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
If you treat them right, yeah. Or they can hide the tumor cell from the T-cells too.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, if you make too many T cells, you can definitely get sick. And especially if they react with normal cells or with something that makes big soluble factors that affect. And that, unfortunately, is one of the main side effects of the therapies is... cause reactivity with normal tissues and things. I mean, there's no free lunch. You start messing with those things.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I mean, 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. Okay. Other people get very sick. And sometimes there can be things which can be fatal. Thank God they're rare.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 CTLA-4 in the 90s. There was this molecule, and it was funny. It looked like a molecule that was the gas pedal of T cells, but this molecule called CTLA-4, and we showed that it was actually not a gas pedal, it was a brake.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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, showed that CD28s and other molecules, like the gas pedal. So the antigen receptor you could think of is the ignition switch. That's all it is.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 CD20A that we showed in the late 80s, was the gas pedal. If you don't push on that, activating through the antigen receptor doesn't do you any good at all. The T cells don't do anything.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Tumors never have, 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 90s. The tumor gets big enough or whatever causes inflammation.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
The innate immune system comes in. The innate immune system has those things that they're called B7 for B7.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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's that says go so the only way that the immune system with solid tumors and this is that we published this there in the early 90s 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 receptors. 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And so they have to expand. And so that's what this, so the T cell receptor sees the ignition switch. And then when you, but nothing happens really until you push on the CD28 molecule, the gas pedal, then they take off. You got to 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I mean, that's 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, obviously.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But anyway, they go find the tumor cells wherever they are and 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
so these tumors are going to grow very fast generally yeah right and and see well they not not that fast it takes years generally it's at the end when they start damaging 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 more degrees of freedom in 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
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
is it is it something where different kinds of cancer are still going to need different kinds of t cells to come to life different they're all they're basically the same same kind of thing 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've got to work on those but anyway there's this other molecule called cta4 which we just which we showed in the early 90s again was a break
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 or something like that, but they'll just grow normally and use up all your nutrients. Yeah. Nothing left for everybody else.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
So you've got to stop that process. And that's what this molecule called C-flav4 does. And so the thing that we figured out in the 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And so that works spectacularly well in some kinds of cancer. just taking the brakes off for a while.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah. Melanoma kills you because it 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. It had to be 100 and whatever, 100. He was cured about seven years ago with immunotherapy of brain cancer.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 used to be a lot of stigma associated with it. Maybe there still is in some cases. But it's an unfortunate thing that happens to us. We have a lot of cells that comprise our body. If they don't aren't controlled.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Is it being tested? 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. It's the first thing you'll get because it's so effective. The drug that we developed in the late 90s, ipilimumab, that was approved by the FDA in 2011, that's given all over the world.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And so when you go with immunotherapy, and also there were 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
It's infused in your blood and you go home and that's it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah. And with blood, most patients, there's some scratchiness, there's some diarrhea, there's some...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 an autoimmune condition and 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 places most time it's not anyway it was 20 but then after we um
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
After our stuff started coming out, Tosco Hanzo in Japan, plus Arlene Sharp and Gordon Freeman at the Dana-Farber discovered this other checkpoint. C-24 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. So the T cell receptor obviously is a positive signal, it's the discharge switch.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
CD28 is the gas pellet, it's another positive signal. CD284 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 worked spectacularly well. As I said, it was a phase one trial, you know, which normally is just safety.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
You make sure you're not killing anybody and then titrate it up until they start getting really sick and then back off a little bit. And that's the way that cancer therapy used to be. So there you prove it's safety. You find the maximum tolerated dose. 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And 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 go up and up and It gets more frequent in the population, but people don't necessarily get sicker. It's not like there's a poisonous level of it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And in melanoma, in the first 14 patients, phase one, there were three whose tumors completely went away, 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 with was unblinded and reported to the FDA.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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% would survive. Now, with just this one drug, 20% are alive at 10 years plus.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
With no other therapy, just one round of therapy, you're done. When Tosca came along with this other molecule called PD-1, which works a slightly different way, but the overall picture's 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. So now we went from a cancer, which was almost uniformly fatal in less than five years till we could cure more than 50% of the people with that.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
It's amazing to me that it works as well as it does, that everything stays under control. Unfortunately, it hits people. It hits a lot of people, way too many. It's hit way too many in my family.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And that's exactly what we're working on now is how do we get that to a hundred?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And unfortunately, I don't want to get into that, but I'm not sure that the drug companies 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. Its whole goal is how do we make that better?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 real? 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 influence the immune system in various ways that they regulate it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And some of them only pop up when you take one off. In one sense, it's whack-a-mole. 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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, you know. So it's all tuned to do that. But anyway, so one of the cardinal rules in performing drug development is
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 sort of thing and understand it mechanistically.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And so that's, I mean, what we're doing is going into humans as soon as we can, as soon as we know it's safe and giving combinations to get biopsies and seeing what happened, what new molecules came out.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Because now we can measure the advances that have been made in biology in terms of being able to do single cell transcriptomics and 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And 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-patient trial. 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?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. So that's the idea is do this iterative thing. That's how we get it from 55% to 100%.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
No, it's not. Well, it depends. I mean, the common thing is the 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. They're different tissues. First of all, that's why it used to be classified solid, you know, and muscle or whatever solid tissue versus leukemias, you know, in the blood.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, I mean, I think in a way we do ourselves a bit of a disservice by calling it like the antibody that we made to CTLA-4. It's the drug. It's not the drug. It's the thing that it's the prodrug. It's the T cell that's the drug. Right. And so that antibody is gone in a few weeks. The T cell is there for the rest of your life.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 neurodegenerative diseases involve dysfunctions in the immune system. If 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I mean, 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 can just do the opposite of what we're doing now.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Maybe we can cure those diseases, you know, and, you know, 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 cancer.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 story. problem more and more. And so single-cell analytical techniques, the ability to take a slide, you know, now to diagnose a cancer, you get a piece of the cancer and you stain it with hematoxin and ESN, you know, you get this purplish
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And what we already know is that the same cell that's here next to the cancer cell is gonna be different than an 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And 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 turn the T cells off. We can figure out how to just turn those molecules off. Myeloid cells, you know,
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But we gotta 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 as the science, as the engineers and the computational people and all that Coming up with all these magical new things that I couldn't even dream of five years ago.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I mean, that's how fast it moves. There's stuff we're doing now that I wouldn't even have guessed that we'd 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, I mean, I've always been fascinated in science and biology and everything. just as a, you might as well do something on the area of something that helps people.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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, 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Cause you know, I mean, I like, 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, you're,
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
A lot of it's drudgery, too, but 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
By the way, I see you have a guitar. Do you play much?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I'll tell you one funny one. I had a knee replacement last, what was it last year? Yeah. Anyway, and Willie, I play with him occasionally, but he asked me to come to Austin. I'm in Houston. His 4th of July picnic's in Austin. So I said, would you come down? I mean, he didn't, but his wife and his harmonica player is a friend of mine. So Jim, come down and join us. I said, I can't.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I just had knee surgery and I don't want to go down there. 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 lake house that 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?
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I said, well, I can't walk very well. They said, well, get a wheelchair. 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 they said, come out. And I said, no, I can't. I can't stand yet.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
I was in a wheelchair, I had a cane. Anyway, Willie got into the gospel. He always closes his concerts with a gospel medley. I saw the light, will the circle be broken? I'll fly away, you know, all the... Great old song. 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And Willie's wife got behind me and said, Allison, get your ass out. So anyway, so I jumped up and took a couple of steps before I didn't even think, you know, I just stood up and had a cane in one hand, a harmonica in the other. And then I realized this isn't going to do because I need both hands when I get out there.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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. Really healed him. Praise the Lord. Evidence. It was not a double blind study, but I saw the light, you know, it was just so perfect. Yeah.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Okay. Bye-bye.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But the common thing is just mutation. the functional classification according to causation can be useful, and for a while it was thought was the real key.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 fix that cut or whatever. But if something happens and that pathway gets locked on, you know, so the doorbell's ringing all the time, you know, the cells just keep dividing.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And the idea was, well, if we could inhibit that pathway, then we cured cancer, right? So this was all the excitement around the early 2000s, 2010 to about 2015 was 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 could cure 99%, kill 99% of the tumor cells.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
It doesn't make any difference because 1% or 0.1% will have another driver and they'll inevitably grow out.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
But now we know it's probably not going to be. It's certainly worth doing because it can prolong life. I, as an immunologist, tend to look at things differently because So the tumor biologists who 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 cancer biologists say, oh, well, those are irrelevant.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
They're passengers, so 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, its purpose is to find things that shouldn't be there.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
They don't care what they do. That shouldn't be on my cells. That cell may have a virus in it and I'm gonna kill it. 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. They're equally important to the immune system. The immune system doesn't know the difference. It just knows there's something different here.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
We better get rid of that guy.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, well, evolutionarily, you know, it's all evolution. And 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
No, I wish we did. Maybe they have a really good immune system. I doubt it.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, 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.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Yeah, not so good for the mice, but...
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Well, 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 If you get out of the sun a lot and you expose your skin to ultraviolet radiation, chances are you're going to get mutations in your skin that can cause melanoma because that's, you know, what the sunlight hits.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
And, you know, if you stay out of the sun, you're probably not going to, get melanoma, although plenty of people, same with 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 it, I mean, you're not going to get lung cancer because the cells divide. There's, there's, there are mistakes.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
Let's go back historically. Let's go back way to the start. There's evidence that the Greeks knew about tumors, and they cut them off. Okay. And so the very first cancer therapy was surgery.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
got it yes and uh 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 in any kind of big way it's already spread to other organs uh in your body prostate same way um so um But if you can catch it early, surgery is pretty effective.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
The next therapy that came along was radiation. The Curies around the end of the 19th century, beginning of the 20th century, Madame Curie in particular, developed radiotherapy. That was quite useful and curative in some cases. Of course, it also caused cancer. People learned about spinogenic effects, but the idea was you blast a cell and give it enough mutations that it can't live.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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 warfare, agents that were developed leading into World War II, ultimately led to some pioneers in cancer therapy.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
In the 50s, you know, applying it to leukemias, childhood leukemias in particular, mustard, I mean, just toxic gases, toxic chemicals that were used to mustard gas, for example. Those were the basis of the first chemotherapies. They kill dividing cells.
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
They cause a lot more mutations. They screw up the DNA as it's dividing and make it so that the cell can't successfully divide without making it. Unfortunately, you could also put in a lot of mutations that will make it more likely to get a cancer down the road. But the bottom line is, with both of those, both radiotherapy and chemotherapy as given, unless you kill every last tumor cell,