IRA FLATOW: This is Science Friday. I’m Ira Flatow. 

For years, cancer treatment has largely involved one of three options– you get surgery, radiation, or chemotherapy, or maybe a combination of those. But in recent years, a new treatment option, immunotherapy, has come on the scene. And it has become the first line preferred treatment for certain cancers. 

Immunotherapy is a class of treatments that use some aspect of the body’s own immune response to help battle cancer cells. It is not a cure-all. In some cases it works dramatically well; in other people, not at all. And researchers are working to try to figure out why that discrepancy is. 

This year the Nobel Prize in Physiology or Medicine went to two researchers who have developed one type of immunotherapy known as the checkpoint inhibitors. And one of them joins us today– Dr. James Allison, Chair of Immunology and Executive Director of the Immunotherapy Platform at University of Texas MD Anderson Cancer Center in Houston. And he’s just back from receiving his award in Sweden this week. Welcome back. 

JAMES ALLISON: Well, thank you. I just got back late last night. 

IRA FLATOW: Well, we hope you had a good time there. 

JAMES ALLISON: Oh, it was wonderful, magical. 

IRA FLATOW: That’s terrific. Also with me today is Dr. Thomas Gajewski. He’s the AbbVie Foundation Professor of Cancer Immunotherapy at the University of Chicago Medicine and heads the Immunology and Cancer Program at the University of Chicago Comprehensive Cancer Center. Thank you for being with us today. 

THOMAS GAJEWSKI: Thanks so much. It’s great to be here. 

IRA FLATOW: Let me ask you, Dr. Gajewski, why doesn’t the body recognize cancer and attack it? 

THOMAS GAJEWSKI: Well, one thing that we’ve learned is that in fact, in many cases the immune system is trying to recognize and destroy the cancer. There can be what we call antigens, or molecules that can serve as recognition points for T cells of the immune system. These are the killer T cells that have within them the capability of destroying cancer. So the immune system is trying to do this. 

But then it gets hung up. And one of the mechanisms that hangs them up are these negative regulatory receptors or pathways that shut the immune system back down. And that’s what is the target of these new therapies that Jim Allison and Tasuku Honjo and others that have followed, called checkpoint inhibitors. That’s what they’re aiming to do, restoring the function of those immune cells that are not quite doing the job on their own. 

IRA FLATOW: In other words, instead of having the cell pass by, you’re able to recognize the cell and attack it. 

THOMAS GAJEWSKI: That’s right. Yeah, so in many cases, your immune system actually has done a lot of the job. It’s been activated. The army of T cells has been expanded. Those T cells have trafficked back to the tumor sites and the different sites of metastasis. And we can find those T cells in the tumor. But they’re sort of stuck. 

And what a lot of the research over the past 20 years has unveiled is what some of those mechanisms are that are holding the T cells back. You now block those. The T cell function is restored. And many patients have a very effective, even complete disappearance of their tumor when that’s done. 

IRA FLATOW: Amazing. Dr. Allison, how did you come to identify that first immune checkpoint that could be used in cancer immunotherapy? 

JAMES ALLISON: Well, we’ve been trying to understand why T cells didn’t work very well in cancer. But I felt that there’d been a lot of efforts made without a sufficient understanding of how T cells worked, to really be precise about them. So we’ve been studying for over 20 years the molecules that are involved. 

And it’s a pretty complex process. It’s not like just flipping a light switch and it goes on. There are a couple of signals at least that you need to start it, one like the ignition switch, which is recognition of the antigens that Dr. Gajewski was talking about. And another one is a gas pedal-like molecule called CD28 that tells them to go. 

But we were studying this in the mid-’90s, or early ’90s. We found there was another molecule called CTLA-4. It first was thought to be another gas pedal. But we showed that it was actually the brakes. And its job is to stop the immune system and stop T cells after a certain point. And we reasoned that they might shut off the T cells before they had a chance to eliminate all the cancer cells. 

And we just had the notion that if we just disabled the brakes for a time, that the T cells might then go after the cancer cells and completely eliminate them. And so after doing the fundamental biology, we then started doing preclinical studies in mouse and model systems for cancer. And this approach worked with just an astounding number of different kinds of cancers in mice. Basically, the tumors just melted away. 

IRA FLATOW: Well, that’s– I’m sorry. That’s my next question. Why does it work? Do we know why it works so well for some people in some diseases, and not for others? 

JAMES ALLISON: Well, those questions best, I guess, be separated a little bit. We know that some cancers respond quite well, because it appears that– cancer’s caused by mutations, ultimately. And the cancer biologists, in previous attempts to target cancer, mutations in cancer, have focused on the so-called driver mutations that make the cell a cancer cell. 

But the immune system, of course, just recognizes things that are different. It doesn’t matter to the immune system whether it’s caused them or not. And so there could be hundreds to thousands of mutations in cancer cells. And those have the potential to be recognized by the immune system in the form of neoantigens, is what they’re called, that are in tumor cells but not normal cells. 

And that’s really what the T cells focus on. And some cancers, like melanoma and lung cancer– melanoma because it’s caused by mutations caused by ultraviolet radiation, and lung cancer and head and neck cancer and bladder cancer and others by carcinogens largely associated with smoking, for example. And those are just sitting ducks for the therapy. They’ve got so many mutations. But it’s not all that, because some people with a lot of mutations don’t respond at all. 

So one of the reasons is that there are multiple checkpoints, as we know now. PD-1, which was discovered about seven years after we did our early work, actually is also expressed as part of the response mechanism, at a later point. And so one of the things is that patients that don’t respond to CTLA-4, for example, respond to PD-1 and vice versa– at blockade and vice versa. And we know there are a few more checkpoints. 

So that’s part of it. But even then, if you combine those two, the response rate in melanoma is about 60%, which is pretty good, considering when we started this work the median survival after diagnosis was 11 months. And there was no treatment at all that ever extended that. 

But still, there are other factors– getting the T cells into the tumor cell. The tumor can have defense mechanisms that keep them out, or once they’re there help shut them down to a microenvironment. So these are things that are all– we’re studying it and learning about it, and have been able to overcome this in several situations, it looks like. But there’s still– we’re early days. It’s still– it’s just beginning, really. 

IRA FLATOW: Mm-hmm. Dr. Gajewski, is this the leading– are we now in the leading kind of immunotherapy, the checkpoint inhibitors? Is this the cutting edge, the best hope so far? 

THOMAS GAJEWSKI: Oh, yes. So in three cancers to date, checkpoint blockade immunotherapy, either alone or in combination with other agents, has become the first line treatment for patients with metastatic disease. That’s in melanoma, in kidney cancer, and in non-small cell lung cancer. And there are other studies, similarly, going on with other cancer types. 

One thing that’s been pursued is now that we have these drugs that are remarkably active, at least in a major subset of patients, is to take more of an unbiased approach, letting the patients tell us what the escape or resistance mechanisms are. So you can imagine, if two patients present, one of them has complete disappearance of their tumor with checkpoint blockade and another no response at all, you might start asking questions. Why are those two patients and their cancers different? Maybe the cancers themselves are different because of different oncogene pathways, mutational events that occur in one but not the other. Some of those pathways could make the tumor immune resistant. 

Those two patients themselves also could be different. The inherited genes that many people think of, genetic predispositions to cancer, we also think there are genetic contributions to the magnitude or the characteristics of the immune response against cancer. So that could be different between patients. 

And then another very important area that’s started to gain traction is environmental differences. And the environmental difference that we’re most excited about is actually the composition of the commensal microbiota, the bacteria that we’re all colonized with that’s highly variable from person to person. And we and others have found patterns in the microbiota that either support efficacy of these drugs or support complete resistance of these drugs. And once we map these with big data sets, computational approaches, then we can develop new strategies to intervene and try and expand the circle of patients gaining clinical benefit. 

IRA FLATOW: So are you saying the microbiome may have a significant impact on whether it responds or not? 

THOMAS GAJEWSKI: Yeah, that’s what the data are telling us so far. So in our own group, in 2015 we had published a paper that described a mouse model where if the only variable was changing the gut microbiota, mice either responded really well to checkpoint blockade or minimally. We figured out by sequencing, not the mouse genes or the tumor genes in this case, but the bacteria genes, we figured out what some of those key bacteria were. And in fact, in the mouse we could then give back a missing bacteria and turn poorly-responding mice into maximally-responding mice. 

So based on that, we and others have profiled the microbiome sequencing in human patients getting treated with checkpoint blockade and have found a similar pattern, which makes it possible now to envision a kind of a probiotic. I don’t want to use the term probiotic, because these bacterial preparations are going to be clinical grade, quality controlled, delivered in special capsules and so on. But it’s made it possible now to envision giving back bacteria to improve the host’s immune response and then make checkpoint blockade work better. So that’s right where we are, at that part of the cutting edge of the field. 

IRA FLATOW: In case you just joined us, we’re talking about cancer immunotherapy with James Allison, 2018 Nobel laureate, and Tom Gajewski. 

Dr. Allison, OK, if you remove these breaks on the immune system, how do you keep it from going too fast and possibly injuring the healthy tissue. You know where I’m going on this. What about the side effects? 

JAMES ALLISON: Yes. Yeah, absolutely. I mean, one of the things that we knew about CTLA-4, that particular checkpoint– the first one, before we went into the clinic– was that if we eliminated the expression of that gene, just took it out of mice completely, they developed this proliferative disease where their T cells couldn’t stop dividing. And it was lethal. 

And so if we had known that when we started, we probably wouldn’t actually– it was before the clinical data work started, but after we started the preclinical studies. But we knew, in thousands of mice we’d injected antibodies without any apparent side effects at all. So we thought maybe it’s time, you know, that it’s out, because if you knock the gene out, it’s never there. And so it might be that that was different. 

Anyway, whatever. It turned out that there were no adverse events in mice. But because of that, there were very, very extensive toxicity studies that had to be performed in non-human primates. And there were also no adverse events seen in them. 

But in the very first patients that were treated, the most abundant, or the most frequent adverse event was colitis, or a very, very bad diarrhea. And there are other things that can happen too– temporary hepatitis, pneumonitis– inflammation of the lungs. Anyway, a lot of inflammatory conditions. 

At first, everybody thought they were autoimmunity. They really don’t seem to be classical autoimmunity, at least, because the patients can be treated with steroids, for example, high-dose steroids to get rid of the adverse events. And then patients are weaned off of that. And they go away. 

Some patients have none at all. But most patients do have some of these adverse events, low grade. Some have these very high grade. 

But we know now that hundreds of thousands of people have been treated, that there are occasionally true, bona fide autoimmunity-type situations. 

IRA FLATOW: Right. 

JAMES ALLISON: Once is inflammation of the pituitary gland. Another one is Type 1 diabetes, occurs in some patients. 

IRA FLATOW: So you really have to study this more to see– 

JAMES ALLISON: You have to study it. Also, the main thing is, though, that it’s generally really manageable in 98% of the patients. 

IRA FLATOW: Wow. 

JAMES ALLISON: But the doctor has to stay on top of it. There has to be really good communication between the physician. It’s not like chemotherapy or radiation therapy, where the adverse events are really predictable and seem to be stereotypical from patient to patient. 

IRA FLATOW: OK, let me just jump in here and remind everybody that this is Science Friday from WNYC Studios, as I rudely interrupt you, Dr. Allison. 

JAMES ALLISON: That’s OK. No, anyway, it’s something that does require careful attention. And the physicians need to be aware of it and equipped to really pay attention and adapt to it as it goes along. 

IRA FLATOW: Let me see if I can get a call in here before the break. Let’s go to Oakland, California. Stephanie, hi. Welcome. 

CALLER 1: Hi there. 

IRA FLATOW: Hi there, go ahead. 

CALLER 1: So my question is around the science comparing solid tumors or the cancers that have already shown some progress versus blood cancers in particular. I’m interested around CLL and myelofibrosis. 

IRA FLATOW: Tom? 

THOMAS GAJEWSKI: Yeah, maybe I can take that, to start. What’s kind of interesting from the biologic perspective is solid tumors, in a way, set up their immune evasion in the context of their microenvironment. So the tumor– each metastasis is kind of walled off and has set up its own micro-domain, figuring out how to evade the immune response. 

The hematologic cancers, blood cancers, the tumor cells are dispersed widely throughout the body. And we’ve modeled this in mice, in collaboration with Justin Klein, one of my colleagues. And the type of immune dysfunction that can happen in those leukemia models is very potent, where the tumor cells are wandering everywhere. They seem to have the capability of grabbing onto all the T cells and shutting them down before they can get the job done. So these kinds of therapies are being pursued in blood cancers. 

Our own view, and the view of some other colleagues in the field, is that we’d have to apply those drugs– the checkpoint blockade drugs– very early, before the leukemia has gotten a chance to inactivate all the T cells in the whole body. There is such a study that’s ongoing, giving some of the checkpoint blockade antibodies anti-PD-1 or anti-CTLA-4 very early, when there’s minimal leukemia. Those studies are still ongoing. But we’ll see if that captures benefit. There are others being done in patients with established leukemia. Me, I’m not so optimistic that those are going to be that successful. 

And one other implication here– I’m not sure if that’s going to continue a new thread of conversation here– is that if the endogenous immune cells are so shut down, this is an opportunity to remove some immune cells, re-engineer them, and infuse them back. And that main therapy is CAR T-cell therapy, which is also FDA approved for some leukemias. And that’s another way to advance immunotherapy for it. 

IRA FLATOW: Talking with Thomas Gajewski and James Alison. We’ll be right back after the break. Our number– 844-724-8255. Stay with us. We’ll be back right after this. 

This is Science Friday. I’m Ira Flatow. We’re talking this hour about cancer immunotherapy with my guests, James Allison, who shares the 2018 Nobel Prize in Physiology or Medicine, Chair of Immunology and Executive Director of the Immunotherapy Platform at the famous University of Texas MD Anderson Cancer Center, and also Dr. Thomas Gajewski. He’s the AbbVie Foundation Professor of Cancer Immunotherapy, University of Chicago Medicine. And our number– 844-724-8255. 

Let’s look toward the future. Let me begin with you, Dr. Allison. What kind of breakthrough do you need? What tools? I gave you the blank check. You just won a lot of money, the Nobel Prize. I don’t expect you to spend it. But if I had a blank check and you could have any equipment or direction to take, what would you like to do? How would you do that? 

JAMES ALLISON: Well, I’d need a lot of equipment. Actually, there– there are instruments that are available now that weren’t available even two or three years ago that we can bring to bear. But what we need to do is– we know the basic rules here. But there is a lot we don’t know. 

As Dr. Gajewski was saying, the tumor microenvironment can be quite different from cancer to cancer, quite different from tumor to tumor. And so it’s very important to get samples of tissues, cancer tissues from patients that are before treatment, on treatment, and look at both patients who succeed and who respond and who don’t respond, and really look at the things that are going on and what happened and what didn’t happen. We’ve got a pretty good idea of what a good response looks like. 

But there’s just too many trials being done where– combination trials now. There are about 2,000 underway. And most of them just have clinical endpoints. And if a patient doesn’t respond, they disregard one of the other components of the combination and move on, without knowing if it did anything. And that’s critically important to understand what’s going on. By doing that, we’ve been able to, in a rational way, propose some combinations in cancers that weren’t responding very well to either anti-CTLA-4 or anti-PD-1. 

IRA FLATOW: Is it simply a question of finding the right combination, an engineering problem, basically? 

JAMES ALLISON: Not really. You have to know what’s up. We know that there are some additional checkpoints. Probably, I would think that CTLA-4 and PD-1 are the major ones. But there’s some minor ones that can play a role. 

I mean, the immune system is very, very complicated. And so there’s ways that it has to be adjusted, and many ways to sort of fine-tune it. But these can differ in the kinds of cancers that it’s expressed in. One molecule, we know for example, is expressed very frequently in prostate cancer but almost never in melanoma. 

And so we’re going to have to face the future, I think, of somewhat personalized therapies that hopefully could be generalized somewhat to the subtypes of cancer, but are based on what’s in that cancer. 

IRA FLATOW: Right. 

JAMES ALLISON: What’s the patient’s body doing to it? And we’re not going to have just one combination that’s going to see everything. I’d bet that for most cancers, it’s going to be some combination of anti-CTLA-4, anti-PD-1, and then maybe one or two other things to really make them. So I think that’s coming. 

IRA FLATOW: Let me ask Dr. Gajewski the same question. What would you do? What do you need? What kind of tool would you like to have? What kind of breakthrough do you need? 

THOMAS GAJEWSKI: Well, yeah, I agree with Dr. Allison. One of the main limiting steps here, or limiting factors is– we call it– the general term is biobanking, where we want to bank these different types of tissues to gain different dimensions of data– the tumor, the blood, the DNA that’s inherited, serum for different factors, the stool for the microbiome, and others– in as many patients as possible treated with these drugs alone and in combination. And that’s the kind of enterprise that– it’s not a great subject for a grant, let’s say, from the NIH, like just a blank check to support banking all of these different tissues, because there isn’t a clean question that can be carved out in a typical grant application format. 

And so our group, others, MD Anderson have been able to start to advance that forward with some philanthropic support, some foundation support to be able to make the discoveries of mechanisms of success versus failure in real patients. And then if we could expand that an order of magnitude, with all the different kinds of cancers, we could end up– I’m thinking we’re going to end up almost with patient-specific or subsets of patients where we say, aha, this mechanism A is your resistance mechanism. And now we have the drug to combine with anti-PD-1 or anti-CTLA-4 for you. And this other group of patients, it’s going to be mechanism B. But to do that, we need lots of data, lots of– 

IRA FLATOW: So you’re talking like a big– it’s a big data question? 

THOMAS GAJEWSKI: This is definitely a big data question. We’ve been capitalizing on that with bioinformatics, core facility. Bioinformatics are computational people that deal with massive amounts of biologic data like DNA sequences, et cetera. And you let the computer tell you. 

I mean, it’s multiple dimensions of data. We have, from what I just mentioned, let’s say six different dimensions of data, all with millions of data variables, projected onto either that patient responded or didn’t respond. And how do you even wrap your mind around that? Well, the computer can do it for you. 

IRA FLATOW: Right. 

THOMAS GAJEWSKI: You say, these are the responders. These are the non-responders. What are the patterns in bladder cancer, lung cancer, melanoma? To do that, you need hundreds, thousands of patients with these multiple millions of data points. And for that, that’s a big enterprise. 

IRA FLATOW: I can see the enormity of the problem and the solution. But before you go, I can’t let you go without saying to my audience, to actually let them know for transparency, that you guys play in a band together. Right? 

[LAUGHTER] 

JAMES ALLISON: Yes, we do. Try to guess the name of it. 

IRA FLATOW: Uh– immuno something. 

THOMAS GAJEWSKI: It’s very close. It’s a similarly nerdy name, relevant to the field. It’s the checkpoints. 

IRA FLATOW: Ha! Absolutely. It could be a highway patrol band by that name. 

[LAUGHTER] 

JAMES ALLISON: Yeah. 

IRA FLATOW: So what instruments do you each play? 

JAMES ALLISON: I play the harmonica. 

IRA FLATOW: You play– Jim, you play the harmonica? 

JAMES ALLISON: I play the harmonica and growler, or sing. 

THOMAS GAJEWSKI: Yeah, and I play guitar. And we’ve been doing this for over 10 years now. It started with three of us sort of goofing around at a conference. Now it’s grown to a band. A solid membership of 10 band members, including a horn section, playing blues and rock. And we play at a few conferences per year. And it’s a lot of fun. 

IRA FLATOW: You’re all scientists, in the band? 

THOMAS GAJEWSKI: All scientists doing cancer immunology, yeah. 

IRA FLATOW: Where’s your next gig, so we can come listen? Or do you– 

THOMAS GAJEWSKI: It’s going to be at the ASCO meeting, the clinical oncology meeting in Chicago in June. It’s the first Sunday in June. And it’s been announced– almost for sure, it’s going to be at Buddy Guy’s Legends in Chicago. So any of you guys coming to the ASCO meeting, you can put that on your calendar. 

IRA FLATOW: OK, well, we’re marking it right now, next summer at that meeting. Thank you both for taking time to be with us today. And congratulations to you, Dr. Allison, on the prize. 

JAMES ALLISON: Thank you very much. 

IRA FLATOW: I hope you can get some sleep in the next few days. 

JAMES ALLISON: I’m going to try. 

IRA FLATOW: James Allison, sharing the 2018 Nobel Prize in Physiology or Medicine. He is Chair of the Immunology and Executive Director of the Immunotherapy Platform at the University of Texas MD Anderson Cancer Center. And Thomas Gajewski, he’s the AbbVie Foundation Professor of Cancer Immunotherapy, University of Chicago Medicine.

Copyright © 2018 Science Friday Initiative. All rights reserved. Science Friday transcripts are produced on a tight deadline by 3Play Media. Fidelity to the original aired/published audio or video file might vary, and text might be updated or amended in the future. For the authoritative record of Science Friday’s programming, please visit the original aired/published recording. For terms of use and more information, visit our policies pages at http://www.sciencefriday.com/about/policies/