Science Friday - Cancer Immunotherapy, Raccoons, Frog Calls. Dec 14, 2018, Part 1

Episode Date: December 14, 2018

For years, cancer treatment has largely involved one of three options—surgery, radiation, or chemotherapy. In recent years, however, a new treatment option, immunotherapy, has entered the playing field. 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. There are several different approaches, each with their own advantages and weaknesses.This year, the 2018 Nobel Prize in Physiology or Medicine was awarded jointly to James P. Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation.” The Nobel committee called their discoveries a landmark in our fight against cancer. Treatments based on their work are now in use against several forms of cancer, with many more trials underway. Still, the approach doesn’t work in all cases, and researchers are working to try to better understand why. How do raccoons keep getting into people’s trash? It might just be one of the greatest unsolved mysteries of our time. No matter what kind of fancy lid, bungee cord, or alarm system we use, somehow these masked creatures always find a way into our smelly garbage. But are they just dexterous or actually smart? Lauren Stanton, Ph.D. candidate in the Animal Behavior and Cognition Lab at the University of Wyoming, joins Ira to talk about testing the animal’s smarts. City mouse and country mouse aren’t just characters from stories—cities are unique ecosystems built by humans, and animals adapt when they move into urban areas. Researchers recently compared the calls of male túngara frogs in Panama that lived in the forest with those in the city. They found that the city frogs had more complex calls and that female frogs preferred these calls—but the less complex calls of country frogs made them easier to hide from predators. Biologist Alex Trillo, an author on the study, talks about the costs and benefits of changing calls for the túngara frog. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

This is Science Friday. I am Iraflato. A bit later in the hour, we'll be talking about cancer immunotherapy. But first, a few months back, the U.N. published a report put together by an international group of scientists explaining what it would take to limit global warming to one and a half degrees Celsius. But this week, the same group of U.N. leaders that commissioned that report chose not to adopt it, but rather say they acknowledge or welcome. I'm appreciated. Insert the euphemistic diplomatic word of your choice. Here to tell us more about that story as well as other short subjects in science. Is Omer Efan, Staffrider with Vox. Welcome to Science Friday. Welcome back. Hi, Ira. So what does it mean that the UN is still arguing over this IPCC report? I mean, it shows just how strong the implications of this report are.

Remember, one of the big findings was that 2 degrees Celsius of warming is no picnic and 1.5 degrees is still a better target. And so a lot of countries are worried that if they commit to this report, they're essentially locking themselves into an actually more aggressive greenhouse gas target. That was the substance of the U.S. State Department's objection to it. They said that they were worried that if they said that they welcomed the report, that would count as a commitment, and then there would be a legal obligation to have a more stringent target.

So there were a lot of countries then, not just a few? Well, it was basically just a few. It was that made the big objection. It was the United States, Russia, Saudi Arabia, and Kuwait that objected to the word welcome, and they wanted it replaced with note. Now, a draft of the report was released this morning, and I think the compromise they really agreed to was essentially that they would appreciate the findings of these scientists. So that kind of checks all the boxes and keeps everybody a little bit happy so they can let the discussions go on.

Oh, Mary, you have to be a diplomatic reporter now to study science. And while that was going on, scientific issues, scientists issued their annual Arctic report card at the annual AGO meeting this week, and that was sort of a blockbuster, wasn't it? Yeah, and if you're the Arctic's parents, you'd probably be very disappointed in that report card. Essentially, what they found was that we're experiencing warmth unlike anything we've seen on record. Last year's report card showed that the Arctic was losing ice at its fastest rate in 1,500 years. This year's report card looked at some of the ecological consequences of that. So they found that the newer, more ice-free Arctic is allowing algae to bloom that can spread toxins that cause paralysis. Alaska has seen an increased sevenfold of shellfish poisoning over the past 40 years.

Similarly, Arctic species like reindeer, caribou, they've seen massive declines upward of half over the past 20 years. Some herds have declined by as much as 90%. Now, those species, they do very good amount year to year, but ecologists are worried that they're reaching such a lot. low levels they might not recover. And they're also seeing melting at a rate they never thought. What would be happening? That's right. And they're seeing so little ice in the summer that they're saying that, you know, we might see a summer ice-free Arctic in the very near future. And on the other side of the world, scientists say they've been studying the health of the Antarctic with the help of some penguins, I understand. That's right. These are Adali penguins,

and they love this tiny crustacean called krill, and they eat so much of it that it actually turns their guano, their feces, bright pink, which actually forms a very nice contrast with the ice around it. Scientists have found out that, you know, they can track these skid marks from space using satellites. And these penguins are actually kind of neat because they live on ice, but they have to breed on exposed rock. So as they watch where these penguins leave their mark, scientists can track the movement of ice. And they've also used this method to actually see to identify new colonies of these penguins in other parts of the Arctic. Is enough that you can see pink from space?

Pinkish brown, that's right. Yeah, and the color actually matters too because they can actually see how much krill these penguins are eating. They're competing now with commercial fisheries that are actually harvesting the krill for fish oil. And so they can make sure that the penguins are actually getting enough to eat by looking at the shade of the guano they leave behind. That's amazing. Okay, leaving planet Earth now, some exciting updates about a couple of space missions. Let's first talk about the new Mars Insight lander. It's already sending back amazing data from the red planet, including sound, which we have a little cut of.

That is the first wind, recording of wind sent back from another world, isn't it? No, Mayor. Yeah, that's right. And it's not actually from a microphone. It's from a device called a seismometer. This is what's on the NASA Insight probe that they're using to study Mars' geology, and it's a device that they want to use to measure Marsquakes. But as they were calibrating and testing the instrument out,

they figured out that they could actually detect some of the movements of air, and they estimate about a 15-mile-an-hour breeze was blowing over the probe's solar panels. And what you hear is actually sort of a pitched-up version of that. The noise it actually makes is very low frequency, and it's hard to hear. But it definitely is making a sound. Wow, that does bring it home, doesn't it? Yeah. And finally, my favorite interplanetary explorer, Voyager 2, has reached another milestone this week, right?

Yeah, it is now the second human-made craft ever. to reach interstellar space. It's essentially escaped the bubble of the sun's particles and is now being bombarded with high-energy cosmic rays. It's about 11 billion miles away from Earth, and it's still sending us data. It's sister ship Voyager 1 went there first, got out first? Yeah, Voyager 1 was actually launched after Voyager 2,

but it was sent on a more sharp or narrower trajectory, and one of the key instruments on it that would detect this has failed, and so it's not really doing as much for us scientifically. And it's amazing, The transmitter on that thing is about 8 watts, something like that. It's just fantastic. They've had to become better at hearing the transmissions because it puts out so little. That's right.

And it's now NASA's longest-running scientific exploration. Fascinating. We hope it keeps going, both of them. Thank you, Omer. You bet. Amir Fon is a staff rider with Vox. And now it's time to play Good Thing, Bad Thing. Because every story has a flip side.

You've heard about the country mouse and the... City Mouse, of course. This story is about the country frog and the city frog. Turns out that male frogs that lived in the city were more attractive to female frogs than frogs that lived in the forest. Oh, the city frogs mating calls, they're called chucks, were more complicated and actually attracted more females. But what are the costs and the benefits of this change? This study was published this week in the journal Nature, Ecology, and Evolution. My guest is an author, on that study. Alex Trio is an assistant professor of biology at Gettysburg College in Pennsylvania. Welcome to Science Friday.

Hi, hello. How are you? Hi, nice to have you. How different were the calls? From the city to the forest, the calls are actually quite different. So in urban environments, males have the ability to increase their call rate, so they basically have a few more calls every minute. And males can also produce calls that are what we call them more complex. And let me just take a second to explain that. So Tungra males have two parts to their call. First, they have a main syllable called the wine, and then a second syllable called the chuck. And males can either call just with a wine, or they can also add a number of chucks to their call. And so urban males have the ability to add more chucks to their call and make them more complex

and therefore change their calls when they are attracting females. And actually we have an example of that. We have a clip of these different chucks. First, we're going to play the forest frog. Wow, just small. Okay, you heard that. Let's play the urban frog. Oh, Dr. Trey, you can hear the difference there.

Yes, there's at least two or three chucks to add it to that call, and that is something that females are really, basically, really excited about. So that makes females much more attracted to those males. I'm going to ask you to tell me why the female were excited by the one with the chucks. Do you know? Yes. It appears that it's basically a quirk of their nervous system, of their neurological system. So females are generally just more excited when males add these extra notes at the ends of their calls, the extra chucks.

And you can actually go to a closely related species of tungarass, where males, do not make chucks. And then you can take that Tungra chak and put it at the end of the call. And then the females of the other species will still love it, love it more than their own calls. So does they, the forest frogs, if they go into the city, can they develop the chuck themselves? Or how did the city frogs get that chuck? So forest frogs can also add chucks to their calls. They just don't add them with the same numbers that the urban ones do. And in fact, part of the study shows that when we transport urban males, urban male frogs from the forest to urban areas, those males do not have the ability to add their game to basically add more checks to their calls. On the other hand, urban males can actually decrease their number of checks in their calls when they're in the forest.

So urban males are more able to basically move back and forth between these two places and rearrange the number of chucks. It's too bad for those guys. Yeah. So, okay, what's the bad news here? What did this tell us about how urban environments might affect animals? Yeah, so basically moving to the city can come with a change in the male frogs environment. There are definitely benefits, and parts of those benefits are the fact that they don't have predators or as many predators and parasites.

Because also these predators and parasites also use these chucks to eavesdrops on the males and then basically get them, get the mus froggy meals. So that's a benefit to the urban male. But now a cause to the urban male is that it's a lot harder for those males to find the females. So they are actually less likely to find a female. And so what they do is they have to up their game. They have to change their calls, make them more complex in order to deal with the females. But that is an adaptive situation because there's also less predators and parasites.

So what do you want to know next? Well, one of the things that basically comes right after the information that we got in this study is whether these populations are still intermixing quite a bit or not. Are these populations quite separated and could this start a strong divergence between the urban populations and the forest populations? Or can we still see a lot of mixing between these individuals, in which case potentially the urban males are going to, the urban phenotype is going to take over? All right. Well, we'll watch for the kids' book, Urban Frog, City, Frog, Country Frog. All right. Thank you. Thank you, Dr. Trio. Alex Trio is an assistant professor of biology at Gettysburg College in Pennsylvania. We're going to take a break, and when we come back, we're going to talk about trying to teach the body's immune system how to fight cancer.

We'll talk about the ABCs of immunotherapy, and we'll take your questions about immunotherapy. We can't prescribe any medicine or whatever individually. Give us a call 844-724-8255. You can also tweet us at SciFry. We'll be right back after this break. This is Science Friday. I'm Ira Flato. 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, And 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, and 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. Well, thank you. I just got back late last night.

Well, we hope you had a good time there. Oh, it was wonderful, magical. That's terrific. Also with me today is Dr. Thomas Gayevsky. He's the Abbey 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. Thanks so much.

It's great to be here. Let me ask you, Dr. Gaevsky, why doesn't the body recognize cancer and attack it? 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 be served 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 Tusukujanjo 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. In other words, instead of having the cell passed by, you're able to recognize the cell and attack it. 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 stucing. 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 very effective, even complete disappearance of their tumor when that's done.

Amazing. Dr. Allison, how did you come to identify that first immune checkpoint that could be used in cancer immunotherapy? Well, we've been trying to understand why T cells didn't work very well in cancer, but I felt that there have been a lot of efforts made without a sufficient understanding of how T cells worked to really, you know, be precise enough. And so we've been studying for over 20 years, you know, the molecules that are involved. You know, 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, you know, one like the ignition switch, which is recognition of the antigens that Dr. I actually 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, we found that there were early 90s, we found there was another molecule called C-TL-A-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 it might shut off the T cells before they had a chance to eliminate all the cancer cells. And I 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 model systems for cancer. And this approach worked with just an astounding number of different kinds of cancer. cancers in mice resulted in. I mean, basically, the tumors just melted away. Well, that's by, I'm sorry, but that's my next question. Why does it work? Do we know why it works so well for some people and some diseases and not for others? Well, those questions best, I guess, be separated a little bit. We know that some cancers respond quite well because it appears that, you know, cancer is caused by mutations, ultimately,

and the cancer biologists in previous attempts to, you know, target cancer mutations, and cancer are 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 it 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 neo-anogens, is what they're called, that are in tumor cells, but not normal cells. and that's really what the T-cells focused on.

And some cancers like melanoma and lung cancer, melanoma because it's caused by mutations are caused by ultraviolet radiation and lung cancer and head and egg 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, PD1, 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, you know, one of the things is that patients that don't respond to C2A4, for example, respond to PD1 and vice versa. blockade and vice versa. And we know there are a few more checkpoints. So that's part of it. But even then, you know, 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 had ever extended that. But still there are other factors, you know, 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. You know, it's a two microenvironment. So these are things that are all, you know, we're studying it and learning about it and been able to overcome this in several situations,

it looks like. But there's still, we're at early days. It's still, it's just beginning, really. Dr. Gavski, 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? 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, sort of 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 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 benefits. So you're saying the microbiome may have a significant impact on whether response or not? 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, The only variable was changing the gut microbiota. Mice either responded really well to checkpoint blockade or minimally. We figured out by sequencing 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, you know, maximally responding mice. So based on that, we and others have.

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 immune response and then make checkpoint blockhead work better. So that's right where we are at that part of the cutting edge of the field. In case you just joined us, we're talking about cancer immunotherapy with James Allison 2018 Nobel laureate and Tom Kaevsky. Dr. Allison, okay, you know, there's

always, if you remove these brakes 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. What about the side effect. Yes. Yeah, absolutely. I mean, one of the things that we knew about C2A4, that particular checkpoint, the first one, before we went into the clinic, was that if we eliminated the expression of that gene, you know, 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, you know, if we had known that when we started, we probably wouldn't actually. It was before the clinical data started, work started, but after we started the preclinical studies, but we knew. And thousands

of mice, we had ejected antibodies without any apparent side effects at all. And so we thought maybe it's time, you know, that it's out because, you know, 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, the most frequent adverse event was colitis or very, very bad diarrhea.

and there are other things that can happen to temporary hepatitis and pneumonitis, you know, 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 autoimmune, at least because the patients can be treated with steroids, for example, high-dose steroids to get rid of the adverse events. and the patients are weaned off of that and they go away. Some, you know, 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 occasion true bona fide autoimmunity type situations. One is inflammation of the pituitary gland. Another one is type 1 diabetes occurs in some patients. So you really have to study this more. You have to study it. Also, the main thing is, though, that it's generally really manageable in 98% of the patients.

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 of it's a really predictable and seem to be stereotypical from patient to patient. Okay, let me just jump in here and remind everybody that this is Science Friday from WNYC Studios. As I rudely interrupt you, Dr. Al. That's okay.

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. Let me see if I can get a call in here before the break. Let's go to Oakland, California. Stephanie, hi, welcome. Hi, hi there. Hi there, go ahead. 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. Tom? 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 microenvironments. So the tumors, each metastasis is kind of walled off and has set up its own microdomain, figuring out how to evade the immune response. So 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-PD1 or anti-C2. 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 threat 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 for some leukemia's, and that's another way to advance immunotherapy forward. Talking with Thomas Skyevsky and James Allison. We'll be right back after the break. Our number 844-8255.

Stay with us. We'll be back right after this. This is Science Friday. I'm Ira Flato. 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 Gaevsky. He's the Abye Foundation Professor of Cancer Immunotherapy, University of Chicago Medicine, 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? What, you know, I'm giving you the blank check.

You just won a lot of money at a Nobel Prize. I don't expect 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? Well, I need a lot of equipment, which we're actually, 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, you know, we know the basic rules here, but there's a lot we don't know. as Dr. Gayaevsky was saying, the tumor microenvironment could be quite different from cancer to cancer, quite different from tumor to tumor.

And so it's very important to get tissues of samples of tissues, cancer tissues, from patients that are, you know, before treatment, on treatment. And look at both patients who succeed and, you know, 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 for, looks like. But there's just too many trials being done where if the combination trials now, they're about 2,000 underway, and most of them just have clinical endpoints.

And if the patient doesn't respond, you know, they disregard, you know, one of the other components of the combination and move on without knowing if it did anything, you know. And that's critically important to understand what's going on. And by doing that, we've been able to, in a rational way, to propose some combinations in cancers that weren't responding very well to either anti-C-C-24, anti-PD-1. Is it simply a question of finding the right combination of an engineering problem, basically? Not really. You have to know what's up.

We know that there are some additional checkpoints. Probably I would think that C-204 and PD1 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 in many ways to, you know, sort of fine-tune it. But these can differ in the kinds of cancers that is expressed in, you know, one molecule we know, for example, is expressed very frequently in prostate cancer, but almost never in melanoma.

And so, you know, we're going to have to face a future, I think, of, you know, somewhat personalized therapies that, you know, hopefully. can be generalized somewhat to the subtypes of cancer, but are based on, you know, what's in that cancer, you know, 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 think, you know, I bet that for most cancers it's going to be some combination of NICTLA4, anti-PD1, and then maybe one or two other things, you know, to really make them. So that's coming. Let me ask that the guy asking 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? I agree with Dr. Ellis. And one of the main sort of limiting steps here, limiting factors, is we call it, the general term is bio-banking, 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 the blood. 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 like a clean question that can be carved out in a typical grant application format. And so, Our group, others, M.D. 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 in 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-PG-1 or ATC-C-2.

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 material. So you're talking like a big, it's a big data question. It's a big, this is definitely a big data question. We've been, you know, 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. Right. You say, these are the responders. these that are non-responders, what are the patterns in bladder cancer, lung cancer, melanomics. To do that, you need hundreds, thousands of patients with these multiple millions of data points. And for that, that's a big enterprise.

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, I actually let them know for transparency that you guys playing a band together. right yes we do try to guess the name of it give me you know something it's very close it's a similarly nerdy name relevant to the field it's the checkpoints oh absolutely

it could be a highway patrol band by that name yeah so what what what instruments do you each play Tom I play the harmonic you play the harmonic you play the harmon you play the Jim, you play the harmonica? I play the harmonica and growl are sing.

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. You're all scientists in the band? All scientists doing cancer immunology, yeah. Where's your next gig?

So we can come listen. 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 a buddy guy's legends in Chicago. So any of you guys coming to the ASCO meeting, you can put that on your calendar. Okay, well, we're marking it right now next summer. at that meeting. Thank you both for taking time to be with us to,

and congratulations to you, Dr. Allison, on the prize. Thank you very much. I hope you can get some sleep in the next few days. I want to try. James Allison sharing the 2018 Nobel Prize in Physiology and 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 Kaevsky, he's the Abbey Foundation professor of cancer immunotherapy, University of Chicago Medicine. Next up, one of the great unsolved mysteries of our time, I mean, besides where did the missing socks go in the laundry, is how do raccoons keep getting into people's trash? Have them around your house, right? No matter what kind of fancy contraption you put on that trash can,

a bungee cord, an alarm system, somehow these urban dwellers always find a way in your smelly garbage. Well, our raccoon's just dexterous. Are they talented? Or are they actually smart? That's what one scientist wanted to know. Her work is the subject of our latest macroscope video, and she joins us now.

Lauren Stanton is a PhD candidate in animal behavior and cognition lab at the University of Wyoming, and she's here with us in New York. Welcome to Science Friday. Hi, Ira. Thanks for having me. So how smart are the raccoon? That's a great question, and that's something that we are trying to investigate in our research.

In our research, we've seen that raccoons are able to solve novel problems that they've never experienced before. We have found that they are able to solve problems in a variety of different ways, which really speaks to their cognitive flexibility. And we see that they solve problems in ways we don't always expect. And I think that really speaks to their creativity and their cleverness as well. So why study a raccoon? And why pick them out? Sure. Sure. So our lab is really interested in the evolution of animal cognition and understanding

how certain cognitive abilities, like learning and problem solving, can aid animals in adaptation to environmental disturbance, like urbanization, for example. So my advisor, Dr. Sarah Benson Amram, who is the PI of our project. She saw raccoons as a really great opportunity to get at these questions. They're highly successful and adaptive. They have expanding ranges. They're invasive in many parts of Europe and Japan. And so they, they're a really good system to try to look at cognition. You know, we also know they have this reputation for being really clever, and there's a lack of information on their cognition.

So, you know, that's kind of why we want to get at this question using them. I was watching the video, a microscope video, on our website at sciencefriety.com slash raccoons, and I was very impressed. And you set up, you were out there in the forest and set up? We explain to our listeners what kind of situation you set up for them to figure that out. Sure, absolutely. We do a couple of different things. One of the experiments that we do is using a puzzle box.

that has a series of latches on it. And the raccoons have to figure out how to open the puzzle box in order to get a food reward. So we use sardines and dog kibble and that's really enticing to them. And so by opening these different doors, you know, the box has many doors on it. So when they open these series of doors,

we can measure how long it takes them to solve and what kind of behaviors they use. And this allows us to quantify their learning ability and their cognitive flexibility. I've also been using a new device that's called, you know, it's kind of a throwback to an old school Skinner box. So if you think about rats pushing levers, and if they push the right lever, they get a reward.

If they push the wrong lever, they get a shock or, you know, some type of negative stimuli. We're not doing that. In this case, they get a small time out. But we've built these boxes that have these scanners in them that allow us to identify the raccoons. They come into the box and they can push buttons to get rewards. So using this box, we can look at the reversal learning. So when we teach them one reward contingency and we change it, can they adapt their behavior and learn a new reward contingency? You know, when you mentioned Skinner Box, I remember when I was in college when B.F. Skinner was very big.

Oh, nice. He had a contemporary name, Conrad Lorenz, who thought, you know, you can't really learn anything in a laboratory situation about the native intelligence. You have to go out in the wild and watch them outside. Do you think that outside, can you monitor them in their native habitat without going to your boxes at all and learn something different, do you think? Well, yes, I mean, we're really interested in studying cognition. in the wild. And so as you've seen the video that's on your website, we pit tag all of our raccoons. So that's kind of like a microchip you use for a dog or a cat.

And when we set up our study sites, we have these scanners in place that allow us to identify the animals. So we're using modern technology to be able to take these studies, these more traditional studies of cognition into the field and study raccoons that are wild and free-ranging. And we're hoping that this lets us get more at their, you know, authentic cognition and, you know, because they're exposed to all of these selection pressures happening right now. And so we want to take that snapshot and, like, really be able to study them in their, you know, more natural environment, which in this case is, you know, urbanized places.

So. I'm Ira Flater. This is Science Friday from WNYC Studios. Talking with Lauren Stanton, who is studying Raccoons in the Wild, and she's, her project is subject of our macroscope video. It's at ScienceFriiday.com slash raccoons. What was the smartest thing you saw them do? I've seen, they've blown me away. couple of cases. What really impresses me is raccoon's ability to cheat. It seems like no matter what kind of puzzle I give them, they always behave in ways that I didn't necessarily predict. So we did try giving them a touchscreen in captivity with our collaborators at the USDA.

And what we found was that when we gave them this touchscreen and they had to pick one side of the touchscreen in order to get a reward, instead of following the cues we were giving them, they would just keep their paw on the screen and be watching the, um, the food hopper where the food would come out, and they would just push randomly, and 50% of the time, they were bound to get it right because of the way we had designed the program. So instead of them, like, paying attention to the signals and cues we were using, you know, they just found their own way to interact with the device. So that's when we decided, you know, to take a step back and say, okay, let's get a bit more old school. Let's go back to just two buttons and see what they do with those. Are they able to teach other raccoons how to work the boxes on the screen?

That's a great question, and also something we're looking at. We're really interested in social learning. Colleagues and I at the University of Wyoming are building social networks based off of our puzzle box data and trying to look at whether or not these raccoons were learning solutions from one another. So hopefully I'll have a better answer for your question in the future. So you have much more field work to do. I do. I do. Well, we have more data analysis and video coding to do from previous experiments.

And then we also have, yes, some more field experiments that are going to take place. And this is a long-term project in our lab. We're hoping that raccoons are going to remain our steady system for these types of questions. I hope for we people who have them coming to our garbage cans. What do you do? What do you do? What's the best way to keep them out, do you think? Oh, you know, I think that constantly just changing up your mechanisms is probably a good idea. There is a chance that they're just going to continue to keep learning. Every time we put out a challenge for them, there's a chance they're going to be able to overcome it.

Are we making them smarter by just giving, do they look at these as puzzles and say, oh, I've got something new to learn here? That is certainly a possibility. You know, up in Toronto, I don't know if you saw this, but they've outfitted the city in these raccoon-resistant trash bins. And, you know, everybody was saying there's no way they're going to be able to get into them. And I don't know for sure what's going on up there. Suzanne McDonald, who's a researcher at York, you know, probably knows all the ins and outs. But there was an article in the Toronto Star recently saying that the raccoons are slowly starting to figure out how to open these trash pins.

So, I mean, it could very well be that we're at this, you know, evolutionary armsways with raccoons. And the more challenges that we put out in the environment, the more, you know, we try to prevent them from getting in, the more they're going to figure out how to get in. So, yeah, another good question for us to look at it. Fascinating work, Lauren. Lawrence Staten, Ph.D. candidate and animal behavior and cognition at the University of Wyoming, and her work is the subject of our latest macroscope video. This is a really cool one. It's on our website at sciencefrily.com slash raccoons. Thank you for being with us today. Thank you, Ira.

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