← Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas
303 | James P. Allison on Fighting Cancer with the Immune System
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Thank you. Glad to be here.
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A
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?
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B
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 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.
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A
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. I know some therapies work better than others. Is it accurate to call it one thing?
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B
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 where it used to be classified solid, you know, and muscle or whatever. Solid tissue versus leukemias. You know, in the blood. And then now it's lung versus colon or bladder versus prostate or whatever. But then with the advent of genomic sequencing and everything, the tendency was to attribute them to the causation. You know, first, crudely, you know, obviously carcinogen induced and obviously virus induced or something, although viruses are a tiny fraction of it. It's not zero, but. 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 was thought was the real key. You know, if, you know, like ras is a molecule that really is involved in a pathway that takes signals outside a cell like wounding or something, and tells the cell, oh, you better divide, because we need to cover up that scrape or that fix that cut or whatever. But if something happens, that pathway gets locked on, you know, so the doorbell's ringing all the time. You know, the cells just keep dividing. And the idea was, well, if we could inhibit that pathway, then we cured cancer. Right? So this was all the excitement around early 2000s, 2010, through up to about 2015, was most of these enzymes that do these things are tyrosine kinases or forms thereof. And so that is if you just inhibit that enzyme, you can cure the cancer by attacking the cause. Turns out, good idea, way too simple because the pathways always have multiple steps 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 you start getting a lot of more mutations. And as soon as that happens, you have more drivers that are called and so you could take one out. It doesn't make any difference. 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.
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A
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.
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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, was not unreasonable and 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 biologist who have the. Take the classical tumor biology view of a cancer would say, oh, well, you got that mutation, let's attack it. And, and. And we'll be done. So we should concentrate on what's going on there. On the other hand, so the mu. There's lots of mutations. The mutations really occur pretty much randomly, and it's when they hit, you know, so they got to hit generally a couple of genes before you got problems. A couple of very types of genes that are very specific. But the other ones, the cancer biologists say, oh, well, those are irrelevant. They're passengers or they're not important because they're not drivers. The immune system, on the other hand, you know, trained as an immunologist, your immune system is just. Its purpose is to find things that shouldn't be there.
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Exactly.
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They're what they do, you know, that shouldn't be on my cells. That's. That cell may have a virus in it. I'm going to kill it, you know. And so then you look at it that way. And those mutations, which to the cancer biologists are not important because they're not the drivers.
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Yeah, okay.
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They're equally important to the immune system. Immune system doesn't know the difference. It just does. There's something different here. We better get rid of that guy.
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You already mentioned that. It's a little bit surprising to you that the body lasts as long as it does and works as well as it does. I mean, I 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.
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B
Yeah, well, evolutionarily, you know, it's all evolution. And unless it takes you out before you reproduce, there's. Evolution doesn't care, you know, if you get cancer when you're 50. Evolution doesn't care.
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Right. But some animal species are pretty good at avoiding cancer. It does seem to be possible. Do we understand that?
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No. I wish we did. No, I think maybe they have a really good immune system. I doubt it.
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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 rare?
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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.
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That's true. But mice, happily, we're able to give cancer to because that's where we do a lot of our tests.
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Not so good for the mice, but.
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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 it just a myriad of various different reasons, or is there some central understanding?
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B
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, the chances are you're going to get mutations in your skin. They can cause melanoma because that's, you know, what the sunlight hits. And, and, you know, if you stay out of the sun, you're probably not gonna get melanoma. Although plenty of people same in lung cancer. You smoke, you know, you're highly, you know, you're a lot more likely to get. But you're not. That does. If you don't smoke, it doesn't mean you're not going to get lung cancer. No, because the cells divide. There's, there's. There are mistakes.
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You know, 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.
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Let's go back historically. Let's go, let's go back way to the start. You know, there's evidence in that the Greeks, you know, knew about tumors and they cut them off.
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Okay.
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And so the very first cancer therapy was surgery.
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Got it. Yes.
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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 in any 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, Madame Curie in particular developed radiotherapy, and, you know, that. That was quite, quite useful. And Curative in some cases. Of course, it also caused cancer. You know, people learned bispunogenic effects, but the idea was you blast a cell and give it enough mutations that it can't live. The problem, of course, is that it also kills the normal tissues, so you got to be careful about that. And then, 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 leukemias, childhood leukemias in particular. Mustard, I mean, just that's 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.
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A
Why are they good at killing cells?
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They cause a lot more mutations, you know, as they. They screw up the DNA as it's dividing and making sure that the cell can't successfully divide without. Unfortunately, you could also put it in a lot of mutations. It'll make you more likely to get a cancer down the road, too, you know, But. But they also. But the bottom line with that, with both of those, both radiotherapy and chemotherapy as given, unless you kill every last tumor cell with those techniques, those approaches to it, the tumor is going to win because it'll just come back. And so you have to blast them so hard with radiation or poison them so much that it makes you sick. Your hair falls out, the lining of your gut comes out. You don't make new blood cells. Your immune system's blown away, you know, and you're sick. And that's, you know, that's. That's what I saw when I was growing up, and my mother and two of her brothers and ultimately my brother. And. And it's. It's. It's. You know, it's. It's a. It's a devastating thing. Not just the cancer, but the consequences of the therapies.
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A
And do tumors spread just because the cells in the tumor sort of get carried around by the blood system or.
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It's a little more complicated than that. There. There are. There are signals that tell them to stay where they are. Those could be lost, but they can also develop things on their surface 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, through the blood. But it's more complicated. There has to be changes that allow them to get into the blood and other changes that allow them to get out of the blood into the tissue that they're going into. So that's a whole nother area. Metastasis of study. That's. That's. That's underwriting.
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A
And my understanding is that you started as a chemist, an actual chemist, more than a sort of biologist or medical person.
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Yeah, well, a biochemist. I got bored with chemistry and 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. 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, I happened. I was lucky enough to have an immunology course as an undergraduate, University of Texas at Austin. And Bill Mandy, the professor, towards the end of the. He was a 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. Okay, screen your cells and see what's going on. Every. The remotest corner of your body, you know, is being surveyed, surveilled, I guess the proper verb by. By the immune system, to make sure nothing's going awry. And that's one of the reasons we're able to keep it all together without going completely bananas. You know, one of the reasons early on, first of all, most of the mechanisms for replicating are pretty damn accurate. But if they're accurate 99.9% of the time, that's not enough.
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Not enough.
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You're gonna get problems.
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And T cells, they're a variety of white blood cells.
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Yeah, yeah, a variety of them. Yeah. Beast lymphocytes are one kind, but they're also macrophages. They're largely, I guess, I would say, two families of lymphoid cells and myeloid cells. Myeloid cells are like macrophages and things like that that engulf bacteria or infected cells or dying debris from dying cells and clean up wounds and all that stuff and help wounds repair. And they have innate signals, they're called, that they can recognize a lot of viruses, a lot of bacterial, just because they have carbohydrates and things on their surface, that is, classes of molecules are different than those found in our cells, mammalian cells. So there's sort of this. We call them the 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 in evolution with development of. Actually not shortly. Shortly after vertebrates and things, but. But anyway, evolutionarily, this other system came along which we call the adaptive immun. You actually have receptors that are made by random recombination of DNA sequences. I don't want to go the details, but basically essentially random processes. 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. It's really a fascinating area of biology that 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, 10 to 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 to the species, you know, so. But. So the population is protected, probably, but not the individual necessarily.
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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 generated.
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No, they're generated essentially randomly.
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Okay.
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These cells come out of the bone marrow. For T cells, they come out of the bone marrow, they go to this organ called the thymus, which sits right above the heart. And there they start developing from this precursor stem cell into 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. There are only 8 to 10amino acids, 8 to 12 maybe amino acids long that are presented in the surface of the sticker. It looks like a hot dog bun. And it's got a peptide in the middle of it. That's. That's. 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 cell. 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. If it's okay, virus that's just infected A cell. And the cell starts making bits of virus and 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, it says, whoops, that shouldn't be there. It'll kill it. It's essentially random.
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So the cell is sort of doing its own annual checkup at all times.
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Exactly. But you 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. That's right.
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Sorry. These are T cells that can be dangerous if they're not in the right kind.
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Yeah. If they're autoreactive, they react with cell 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, can be damaged, like for measles and stuff, you know, down the road. But anyway, basically, they're pretty damn good though.
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A
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. Out of.
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B
Yeah. How many stars are there? 10 of the.
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A
Well, there's a lot of stars, but stars are pretty similar to each other. There's 10 to the 22 stars out there, but, you know, they're. They're not that different. There's no lock and key in there. I mean, I guess that's my question. That your talk about receptors reminds me of people who are trying to study smell and how, you know, we're. We're sensitive to different kinds of molecules. Is it a similar kind of thing going on?
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B
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.
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Yeah.
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Here you've got all these different ones that are flowing all around. All you need to do is trigger one.
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And so the job of a T cell is to understand what the normal healthy cells are like and, and target Anything that is not that.
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Exactly. Not self recognition. That's what it's called. Very philosophically, a very. How do you recognize not self.
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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.
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Yeah, that's first of all, because the cancer cells are not necessarily all that different early on, especially, although they get weirder and weirder with 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 cells guard built into the cell or mechanisms for detecting mutations. And 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 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 in order to get it. That's why some people with retinoblastoma gene, for example, if you have two copies of that, kids get tumors of the eyes when they're about 2 years old. It's a devastating disease. But in other kinds of cancer, you don't get them in your germ line, but you can get them in your somatic cells. And if you lose the RB genes, that makes you a lot in a cell, that makes that cell a lot more likely to get cancer.
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A
That helps. Because I did have the question, you know, do tumors or do cancer cells defend themselves? You know, they don't. They don't pass on their genes in some sense. But I guess the answer is. But they're versions of or made of ordinary cells which do have defense mechanisms.
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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 there's a wound and 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 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 they're myeloid cells there that are trying to stop the T cells from killing tissue because they're just doing what that's their normal functions, 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. 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. There used to be B cells in T cells. Now they're T cells specifically. First there were two kinds and there were five kinds. Now there are about seven kinds. The truth is that those kinds are just constructs that we make up. Yep. In biology, it's a continuity, you know, it's just a continual spread. And 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, you know, thing to help the immune system rather than hinder it.
- [29:41]
A
So one impression I get from reading about these or talking to people is that everything is about switches turning things on and off. 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.
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B
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.
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A
How much, you know, it sounds like with the receptor stuff on the, on the wall of the T cell, that's. That's right down to the level of atomic and molecular structure. Right. Is it, is it very different how we're studying that now than when we're in like 1980s or whenever it was like, has the technology Changed things.
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B
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 interested in immunology was what is the antigen receptor? What is it that the T cell uses? And nobody knew what it was. And so I put on my biochemist hat and said, well, what should such a molecule look like? And worked it out and published that for the first time in 82, 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. How they gives you the combining site. But how is it presented? And so there was this. 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 buns 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 could present it. If you don't, you won't. So, you know, that's another. If you can't present a peptide even though it's there and it's from a cancer, then the T cells aren't going to see it.
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A
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 bit.
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B
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, the new work from the Nobel Prize this year, David Baker, for example, and 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.
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A
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.
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B
Yeah, I'm one of these old school guys that thinks hypotheses are useful.
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A
Yeah.
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B
Now it's get a whole bunch of data and try to pull something out of it, you know.
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A
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?
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B
Yeah, pretty much. Pretty much.
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Those are the things that have 10 to 17.
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B
That's really helping with vaccine design.
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A
Right.
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B
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 and neck cancer by the HPV vaccine. If it was, people would just use it. More importantly in the clinical realm are therapeutic vaccines now. And we understand, we're beginning to understand enough about the antigens that are induced by the mutations where we can begin to come up. This was something was greatly informed about 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 mean they're gonna. We're gonna. They're gonna. I think we're gonna come up. There's going to be eventually a small set of adapters you know, you could use. It'll have all the signals that you need to properly activate the innate immune system and all that. But you put your specific thing in the middle of it and we can generate a vaccine and weeks pretty good.
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A
I mean, is this, is this part of the sort of CRISPR revolution of gene editing?
- [35:08]
B
That's part of it, yeah, 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, seeing if you can initiate or terminate an immune response by okay, you know, manipulating things. But, but yeah, it's that and just all the work that went in developing about the coronavirus vaccines, the COVID vaccines, but that, 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. 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. That's coming along. I think that preventive vaccines, Pretty soon we're going to be able to maybe protect people that have what's called, oh, what is it? Lynch syndrome. They get a lot of polyps, you know, 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. You know, BRCA mutations are associated with. In women with breast cancer and ovarian cancer in 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 could prophylactically treat the population. For most cancers. You're gonna have to come up with something that's really powerful and allows you to jumpstart a response as soon as you detect it. And I think we're getting close. We're not there yet, but I was.
- [37:28]
A
Actually going to ask about the role of simulations. I mean, in physics and astronomy, of course, that's what we do all the time. We simulate things. We test them against the data. I've always had the impression that in biology, the state of the art was that biological things are too complicated to do that and too specific and too individual. So we have to actually test the pharmaceutical in a living thing rather than just putting it on a computer.
- [37:52]
B
Yeah, I mean, we're still there, although it's better now. We could guess, we could make educated guesses. Now we can't get exactly there.
- [38:04]
A
So, okay, so we have this basic security force in our body of the T cells roaming around looking for interlopers. You mentioned a little bit about this already. But why is it that they aren't better at attacking cancer? And how can we make them better? That seems to be the project, right?
- [38:23]
B
Yeah. Well, again, it's because one of them is big and it's the largely they're individual. So your tumor has mutations that nobody else's has. 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. And if you lose expression of MHC molecules, then they're invisible to the immune system. The tumors still be there, still making 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. 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 ways. There are other ways around that that we're going to come up with. But. But that's one easy mechanism. Another one is that one of the main ways that tumors kill tumor cells is by making gamma interferon, which is a cytokine that, I mean, you've heard of. But one of its activities, besides helping protect you against viruses, it'll causes tumor cells to quit dividing and can kill many of them. But if you lose anything along the receptor downstream of the gamma interferon, the thing that detects gamma interferon and tells the cell it's around, if you mutate anything in that pathway, then that doesn't work anymore either. And so the T cells can make all the gamma interferon they want. The tumor won't, you know, won't respond to it. So there's that too.
- [40:12]
A
So what is our goal as immunotherapists? Are we trying to teach the T cells to ignore some of these?
- [40:21]
B
Well, first it's just to get the T cells. Yeah, that's the. And then secondly in importance is do 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 it's. How do we deal with these things that. That comes down. So it's not that you could get the T cells to do any better, but you could come up with ways of making them work at a distance. You know, it's kind of hard to explain, but a different type of T cell, they'll make 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 gammas 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, that's. We could show that happens in animal models at least. I'm pretty sure it happens in people as well.
- [41:30]
A
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.
- [41:38]
B
Yeah, that's 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 and. But what we found started what I mean we. I'm speaking they're not as just me but the field began to realize is the tumors which don't respond well to T cell based therapies usually have really large populations of myeloid cells in them. So that raised the hack, you know, raised the interest. And sure enough, you can show that the myeloid cells can inhibit T cells. And we've 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 rise to some more strategies where you target the myeloid cells. But you're gonna have to do both, particularly in things like pancreatic and glioblastoma.
- [42:32]
A
What are the myeloid cells? What's their role when everything is going.
- [42:35]
B
Well, 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 generally handymen. They're just sort of general handymen that do whatever fixer uppers or you need. But they can get in the way.
- [43:11]
A
And they have this spin off effect that they can basically communicate the existence of a tumor to the T cells.
- [43:18]
B
If you treat them right. Yeah. Or they can hide them from the tumor cell too. I mean they can hide the tumor cell from the T cells too. Right.
- [43:27]
A
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.
- [43:36]
B
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 a big soluble factors that affect. And that unfortunately is one of the main side effects of the therapies is cost reactivity with normal tissues and things. But I mean there's no free lunch. You know, you start messing with those things. I mean most. I mean it's not, it's not that it always happens. I know of at Least one marathoner who got melanoma and went through the whole course of therapy and never missed a race.
- [44:16]
A
Oh, wow.
- [44:17]
B
You know, okay. 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 while you still got time.
- [44:39]
A
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.
- [44:53]
B
Drugs in the form of. Right now, 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. You know, there was this molecule, and it was funny, it looked like a molecule that was the gas pedal on T cells, but this molecule called CTLA4. And we showed that it was actually not a gas pedal. It was a brake. Ah. And there's a people that called it a gas pedal. What they did was they had T cells that put them in culture, activate them, and then add an antibody, and they'd get more. And they said, okay, well, that's a gas pedal. That's what we did early in the 80s, show that CD28s and other molecules like the gas pedal. So that antigen receptor you can think of as 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 CD28 that we showed in the late 80s, you know, was the gas pedal. And 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. Tumors 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. 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 called. They're called B7, for they could be called Frank. It doesn't matter. I mean, it's just the name means nothing. But they bind a CD28 and that's that says go. So the only way that the immune system was solid tumors, and this is, we published this again in the early 90s, was when you. That they grow until there's tumor cell death and the innate immune system comes in and primes the T cells and then you start generating T cells. But the thing is, you probably got 10 to the 10th, 10 to the 9th different, nobody really knows for sure, but different T cells in your body with different receptors. 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. And so you have to. They have to expand. And so that's what this. So the T cell receptor actor sees the, you know, ignition switch and then when you. But nothing happens really until you push on the CD28 molecular gas pedal, then they take off. You 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. 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 let 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 exaggeration, obviously. But anyway, they'd 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. And so these tumors are going to.
- [48:38]
A
Grow very fast, generally.
- [48:39]
B
Yeah, right. And, and see. Well, not that fast. It takes years. Generally. It's at the end when they start damaging.
- [48:46]
A
Okay.
- [48:47]
B
That the problem. I mean, a lot of tumors can 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.
- [49:04]
A
Is it something where different kinds of cancer are still going to need different kinds of T cells to come to life?
- [49:11]
B
They're all different. They're basically the same kind of thing. So there's commonality, but it's those myeloid cells again that 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 CTLA4 which we just, which we showed in the early 90s again, was a break. And so at the end of that expansion phase, that CTLA4 molecule starts coming up and stops the T cells from dividing. They've got to stop or they'll. 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, something like that, but they'll just grow normally and use up all your nutrients and nothing left for everybody else. So you got to stop that process. And that's what this molecule called C float 4 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 get 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.
- [50:26]
A
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.
- [50:41]
B
Yep. Melanoma kills you because it ends up in the. The liver, the bone, or the brain. Jimmy Carter had a melanoma in his brain. He got immunotherapy, was cured, lived to be 100 and whatever. 100.
- [50:57]
A
Okay.
- [50:58]
B
He was cured about seven years ago with immunotherapy of brain cancer.
- [51:03]
A
So I guess that that answers my next question, like, how much is this in the clinic now? Is there a pill that you can take? Is this growing? Is it being.
- [51:10]
B
No, it's not. No. It's all over the world. There are millions of people, literally, that have been treated, in fact, in melanoma. Now, immunotherapy is pretty much the standard of care, is the first thing you'll get because it's so effective. The drug that we developed in the. In the late 90s, apilimumab, that was approved by the FDA in 2011, that's given all over the world. As I said, millions of people have been treated and. And it cures, overall, by itself, about 20% 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. And so when you go with immunotherapy, and also there are some indications that maybe it was immunogenic because it has a lot of mutations. But any event in our, with our drug, 20% of people are cured by one or two injections of an antibody. The therapy, by the way, is you sit in a chair for about an hour and they run a, you know, there's a drip bottle with a drug in it, it's infused in your blood and you go home. That's it.
- [52:25]
A
And that's better than chemotherapy as we know it.
- [52:28]
B
Yeah. And with luck, most patients, there's, you know, there's some scratchiness, there's some diarrhea, there's some, some stuff, but usually nothing really bad. Occasionally there can be bad stuff. Even, you know, patients, some patients get type 1 diabetes, which is an autoimmune condition. It may be they already had it borderline or didn't know. Just makes it worse. But I mean, there's a downside. A lot of patients, most of them, it's not. Anyway, it was 20%. But then after we, after we started our stuff started coming out. Tosco Hanjo in Japan, plus Arlene Sharp and Gordon Freeman at the Dana Farber discovered this other checkpoint. C24 was the first checkpoint, defined as a cell intrinsic, a molecule on the surface of a T cell itself that helps give a negative signal. Okay, so the T cell receptor obviously is a positive signal. It's the district switch. CD28 is the gas pellets. Another positive signal. C24 says stop all that stuff, it's time to quit. And so that's the one we chose to focus on was, you know, can either make the other ones better. We chose, let's just take the brakes off, let's disable the brakes. And it works spectacularly well. As I said in the phase one trial, you know, which normally is just safety. 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. You know, how far can you go before you make people sick? And then you give that dose and you give it until all the tumor'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, you might get. It gets more frequent in the population, but People don't necessarily get sicker. It's not like there's a poison, poisonous level of it. And with in melanoma, in the first 14 patients, phase one, there were three whose tumors completely went away. You know, which was just unheard of at the time, particularly in melanoma, because in 2011, when the phase one, phase three trial. Sorry, that I was associated with, 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%.
- [55:31]
A
Yeah.
- [55:32]
B
Would survive now with just this 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 Pisces. I mean, the gold standard clinical trials, 10 years follow up, 55% of the patients were still alive.
- [56:18]
A
Wow.
- [56:20]
B
So now we went from a, from a cancer which was almost uniformly fatal in less than a 5 years till we could cure more than 50% of the people with that.
- [56:33]
A
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 like.
- [56:48]
B
And that's exactly what we're working on now is how do we get that to 100.
- [56:52]
A
Yeah.
- [56:52]
B
And unfortunately, I don't want to get in there, but I'm not sure that the drug, drug companies seem to be happy with 55% or so.
- [57:00]
A
Yeah.
- [57:01]
B
Anyway, it gets harder now, but, but, but that is the question, right? I mean, to me that's, that's why we have this, this thing called. We have this institute that's been founded in Anderson, and its whole goal is how do we make that better? Right. And the way you make that better again is by bringing the myeloid cells in there. What are the ways, what are the things that are really. Now we know, for example, there are a lot more of these things called checkpoints, probably. I mean, there's 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 and one sense it's whack a mole, you know, you take one off and another one. Because the immune system tries to regulate itself. I mean 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 what it shouldn't are too devastating particularly, but kills you when you're young, you know, so it's all tuned to do that. But anyway. So what are the cardinal rules in farming 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 get one of the other ones. And so we've got to get off of that, you know, off of that sort of thing and understand it mechanistically. And so that's, I mean what we're doing is going into humans as soon as we can, as soon as we know it's safe and giving combinations to getting biopsies and seeing what happened and what new molecules came up. 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. 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, 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, we add Vista, then see if that works, you know, so that's the idea is do this iterative thing. That's how we get it from 55 to 100%.
- [60:15]
A
And do I get my impression is. Or my guess would be that this kind of therapy might also have the benefit that can. You know, thinking of vaccines as an analogy, it sticks around in the body and prevents what's coming next.
- [60:30]
B
Yeah, I mean, I think in a way we do ourselves a bit of disservice by calling like the antibody that we made to CTLA 4. That's the drug. It's not the drug. It's the thing that. It's the pro drug. It's the T cell that's the drug. Right. And so that antibody is gone in a few weeks. The T cell's there for the rest of your life.
- [60:52]
A
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?
- [61:19]
B
No, I think, no, that's. That's an excellent question. But I think that if we can learn how to resist reverse this, we could treat autoimmunity. There's increasing evidence that a lot of neurodegenerative diseases involve dysfunctions in the immune system. 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. 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 oversimplifications. You just do the opposite of what we're doing now. Maybe we can cure those diseases, you know, and you know, so that. No, we, our 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.
- [62:16]
A
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 us that for us.
- [62:28]
B
I think, you know, of course I'm biased, but I think that it's a wonderful time to be doing this work. And it's become a systems biology problem more and more. And so single cell analytical techniques, 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 you said, you know, you get this purplish thing that you could look at shapes. The pathologist could say, that's a cancer. That's not. There's some immune cells over there. Now we can look at that, and by doing some different analytical techniques, we 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. It's in the blood. And so now we can start to unravel what are 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. To the T cells off. We can figure out how to just turn those molecules off myeloid cells, you know, then, you know, but we got to know what they are first. I bring that up because I was just discussing with one of my postdocs two molecules of that sort that we recently found that we're in the process of trying to do that with. But as the science is, the engineers and the computational people and all that are coming up with all these magical new things that I couldn't even dream of five years ago. I mean, that's how fast it moves. There's stuff we're doing now that I wouldn't even have guessed that we'd be doing five years ago that it's. 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. Everything is just as a. You might as well do something on them area of Something helps people. Yeah, because, you know, I mean, I like, 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. And it helps people, too. And so I think that, you know, it's a lot of. It's drudgery, too, but. But it's, you know, it's just puzzle solving. And 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.
- [65:27]
A
It's exciting times. Absolutely. Jim, Allison, thanks so much for being in the Mindscape podcast.
- [65:31]
B
Thank you. By the way, I see you have a guitar. Do you play much?
- [65:35]
A
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.
- [65:46]
B
I'll tell you one funny one. I had a knee replacement last. Was it last year? Yeah. Anyway. And really, I play with him occasionally, but they 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. His wife and his harmonica player is a friend of mine, said, jim, come down, join us. I said, I can't. I just had knee surgery, and I don't want to go down there. And I said, well, we just happened that they were playing in this place called the Woodlands, which is just north of Houston, near this lake where I have a lake house. And 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? We, you know, I said, well, I can't walk very well. I said, well, get a wheelchair. Yeah. I said, okay. Okay. So my son got a wheelchair. We got some friends, we went down, wheeled me in. I'm still on the edge of the stage. And so I was waiting to play, but I still wasn't sure I could go out there. And one song came by, and, you know, they said, come out. And I said, no, I can't. I can't stand yet. I had it. I was in a wheelchair, had a cane. Anyway, Willie got into the gospel. He always closes his concerts with a gospel medley. I saw the Light Will Circle, being broken, I'll Fly Away, you know, all the great old songs. Anyway, so that's so much fun to play. And. And, you know, he said, you know, Mickey, you know, waves me out there. We had a microphone for me. Willie's wife got behind me, said, allison, get your ass out. You know, and 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 I had a cane in one hand, a harmonica in the other. And then I realized, this isn't gonna do because I need both hands when I get out there. So I turned and I threw my crane behind me and then turned back around and took a couple of steps towards the mic. And this woman screamed, he's healed. Willie healed him. Praise the Lord.
- [67:56]
A
Evidence. It was not a double blind study.
- [67:59]
B
But some data there, and it really starts to. I saw the light, you know, it was just so perfect.
- [68:06]
A
Congratulations on being 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 Mindscape podcast.
- [68:14]
B
Okay, bye. Bye. Thanks, Sam.