Paul Rand: For decades, doctors have had a fairly straightforward strategy to treat cancer. Find the tumor and destroy it with radiation or chemotherapy. But what if the most powerful weapon against cancer isn't a drug engineered in a lab? What if it's already inside your body, deep inside your gut?

Thomas Gajewski: So then we did all these experiments and we found all the difference was attributed to the microbiome.

Paul Rand: That's Tom Gajewski, a professor of pathology and medicine at the University of Chicago. He's one of the world's leading pioneers in cancer immunotherapy, a treatment that teaches immune systems to hunt down and eliminate cancer cells.

Thomas Gajewski: These drugs then, they don't target the cancer cells directly. They're unleashing the patient's own immune response. Once the tumor is eliminated, or let's say largely eliminated, the immune response persists as a memory response. And so if the tumor starts to rise up again, it can get knocked down again and the immune system can retain the upper hand.

Paul Rand: Immunotherapy is promising, but it only works for about 20 to 40% of all patients. So Gajewski and his team are trying to understand why. And it turns out that it might come down to what's living in your gut.

Thomas Gajewski: But there's a component of environment that we realized we could measure, which is the composition of bacteria in the gut. And this is called the gut microbiome. And when we started this, there was a field emerging demonstrating that the composition of bacteria in the GI tract and in the gut can regulate the whole immune response in the host.

Paul Rand: If scientists could solve this piece of the puzzle and improve treatment success, immunotherapy could soon be the future of cancer treatment as we know it.

Thomas Gajewski: I can envision a world where we're infrequently using chemotherapy so long as we've made all the right discoveries so we can accomplish these things.

Paul Rand: From the University of Chicago Podcast Network, welcome to Big Brains, where we explore the groundbreaking research and the ideas that are changing our world. I'm your host, Paul Rand. Join me as we meet the minds behind the breakthroughs. On today's episode, how the gut microbiome is the next frontier in cancer treatment and what it will take to make immunotherapy work for more patients. Bold and curious. These words describe the guests that you hear on big brains who are shaping the future of research. The University of Chicago is launching a new campaign called Chicago Minds to further advance this kind of groundbreaking work and expand the university's global impact.

Paul Rand: I wonder if we can start off by just having you simply give folks a baseline understanding of how cancer cells work.

How do cancer cells work?

Thomas Gajewski: So cancer develops from normal cells when there are gene mutations that lead to aberrations that cause less controlled proliferation and accumulation of cells. And so they’re caused by carcinogens usually, sometimes inherited genes, but the alterations are in molecules that control signals and events related to cell growth and survival. And so those cells accumulate then and then they learn to spread and so on.

Paul Rand: My first question really is, is understanding if immune systems are fighting off cancer cells right now without any help from a doctor?

Thomas Gajewski: So it’s interesting to note that those genetic abnormalities that happen in cancer, these mutations in genes, they also lead to changes in proteins that the immune system is capable of recognizing as foreign, just like the immune system would recognize a virus or a bacteria. So the capability is there, but somehow that doesn’t always happen on its own in the given individual.

Paul Rand: And so why doesn’t it finish the job? What’s stopping it?

Thomas Gajewski: Yeah, so we’ve been thinking about that for a number of years. Back in the ‘90s when I worked in Terry Boone’s lab in Brussels, Belgium, doing my research fellowship where I got drawn into the early cancer immunology field. They had found in a given patient you could make a tumor cell line that you grow in the lab and from the blood you can isolate immune cells, T-cells of the immune system, grow them up, put them together in the dish, and the T-cells would kill the tumor cells. So the capability was there in the patient, but somehow it didn’t all come together inside the patient. There was some barrier.

Paul Rand: So we’re going to spend a lot of time talking about immunotherapy. And I wonder if you could, just like you did with cancer, give us a baseline understanding of immunotherapy.

What is immunotherapy?

Thomas Gajewski: So let me explain a little bit what we learned about that disconnect, why the immune system was not eliminating the tumor on its own. And this took a whole series of studies from the laboratory to the clinic. The breakthrough happened when we started to study real tumors in real patients and did biopsies and used sort of emerging higher level genomic techniques to understand everything that was going on in the tumor site. We call it the tumor microenvironment. Tumor microenvironment has cancer cells, but it also has these other cells from the host that support the tumor and then various numbers of immune cells. And what we found was that there was a subset of patients in whom the immune cells did enter the tumor and they were trying to destroy the tumor cells. So it’s almost like an autoimmune reaction against the cancer. But then they were held up.

So it became clear that there were inhibitory pathways that were turning the immune cells back off. And so that was kind of a major breakthrough. And that phenotype, we call that the T-cell inflamed tumor microenvironment or it’s nicknamed hot tumors. 

Paul Rand: Right. Okay.

Thomas Gajewski: That phenotype, broadly speaking, can be seen in a third to a half of patients with different types of cancer. The rest of the tumors, they escaped the immune response by not allowing the T-cells in. So the immune cells couldn’t get to the important site, which is the tumor microenvironment, to have access to the cancer cells to destroy them. So we’ll put that problem aside for now.

Paul Rand: Understood, okay.

Thomas Gajewski: Yep. But the hot tumors, what became clear was these negative regulatory pathways could be defined and then drugs could be developed to block them. So it would release the breaks on the immune system to allow the immune cells to continue the job. And that’s where major successes have happened in the clinic.

Paul Rand: Okay. So most probably folks probably understand that chemotherapy and radiation are attacking the cancer, but immunotherapy actually never touches the tumor. And I wonder if you can talk about why that difference matters so much for the person that’s actually going through it.

Thomas Gajewski: Yeah, it’s interesting. So these drugs then, you’re right, they don’t target the cancer cells directly. They’re unleashing the patient’s own immune response and they’re blocking, for the most part, they’re blocking these negative regulatory events. The main target is a molecule called PD-1 that was identified originally by Tatsuku Hanjo in Japan. He was a co-recipient of the Nobel Prize in medicine for this field, along with Jamalison, who’s at MD Anderson Cancer Center now, identifying these key negative regulators that could be drugged with agents that block them. So when we give these drugs to patients that target PD-1 or CTLA-4, that’s the molecule Jamalison uncovered, the inhibitory signals are released. The immune cells can become re-functionalized, they expand, they start to outnumber the tumor cells and then attack the tumor cells and kill them. So the interesting parts about this are that the immune cells are normal cells.

So there’s an attractiveness targeting your own host immune response that is invariable. It’s constant in the host. The cancer cells can mutate, they can evade chemotherapy, they can evade some other drugs that we give, but here by targeting the host, the host can gain the upper hand, the host immune response. Second thing is that the immune response has immunologic memory. That’s the basis of how vaccines work. You get a vaccine, you have a memory immune response so that if you ever see a virus, you’re protected against it. Well, same thing here. This endogenous immune response, once the tumor is eliminated, or let’s say largely eliminated, the immune response persists as a memory response. And so if the tumor starts to rise up again, it can get knocked down again and the immune system can retain the upper hand. These are very attractive properties.

Paul Rand: And so if the person is going through this, it’s a very different experience of being treated, isn’t it?

What are the side effects of cancer immunotherapy?

Thomas Gajewski: It is. So many people are familiar with common side effects of chemotherapy drugs. Some of them cause hair loss or nausea or diarrhea and so on. The immunotherapy doesn’t translate into these typical side effects that you might get with chemotherapy. There are side effects that can happen, but the side effects, as you might imagine, because you’re revving up the body’s immune response, the side effects are inflammatory. You can get kind of overshoot or let’s say collateral effects on normal tissues, and there can be inflammation in normal tissues. And many patients don’t have any side effects, but when they do happen, they’re inflammatory in nature. The easiest one to wrap your head around is a skin rash where immune cells in the skin, they might expand kind of like you would get with an allergy, a contact allergy. So there can be a visible rash and itching, and that can be treated with topical steroids and things like this.

So very different side effect profile. But it’s also interesting that patients who have important side effects, they’re also more likely to have a clinical response with tumor shrinkage. Because their immune system is maybe a little bit more trigger happy than patients who don’t have side effects. 

Paul Rand: So maybe it’s a good sign.

Thomas Gajewski: Yeah. So we’re not afraid of the side effects. When we do clinical trials of new immunotherapy drugs, if there are no side effects, we’re a little bit worried. We want to see some evidence of immune activation in the patient when we’re developing new drugs.

Paul Rand: Well, one of the things that really struck me is that you talked about when you came into this field in the early 1990s, you said the field was closer to a religion than a science. And I wonder what you meant by that and when that actually moment had stopped being that way.

Thomas Gajewski: Yeah, that is how it felt at times because we had this observation that I mentioned earlier that it was possible to obtain T-cells from the patient, immune cells, and cancer cells, put them together in a dish, and the immune cells were capable of killing the tumor cells in a laboratory experiment. So there were believers and non-believers. There were believers who thought it should be possible to make that happen in the patient if we developed the right interventions. It should be possible to have the two come together, the immune cells to gain the upper hand and then to destroy the cancer. So that’s why it became a field of hardcore believers and it felt like a religion. Interesting. And we just had to keep working at it. And then there were the traditional chemotherapy, radiation therapy people who thought that the folks working in the immune field were peripheral, tangential.

It was almost a cult of people working on the immune system side. The immunotherapy talks with early drugs at the major conferences. They would be on the last day when most attendees had gone home in a room all the way in the back of McCormick Place with 12 people. And the transformation happened when drugs to target these negative regulatory pathways became effective and suddenly…

Paul Rand: Tom, what year was that all happening?

Thomas Gajewski: Yeah, and so this was in the 2000s.

And so when the first, we call it checkpoint blockade immunotherapy drugs were becoming tested, and these were in phase one clinical trials. What phase one clinical trials are, what it means is the first in-man test. You don’t even know a dose to give. You have no idea if it’s going to be effective. The goal of phase one trials is just to identify tolerability, understand the side effects, and then figure out a dose that you could then test in patients and then find signs of efficacy. And that’s called phase two. Phase three clinical trials when you compare the new drug to some old standard of care. So in phase one clinical trials of these first immunotherapy drugs, end-stage patients with the disease I work on, metastatic melanoma, end-stage patients who otherwise would’ve gone to hospice, 30 to 50% of them had tumor shrinkage and a bunch of them had complete elimination of their tumor in a phase one clinical trial.

So the whole oncology field and big pharma field woke up to those results, and everybody climbed on board and accelerated.

Paul Rand: If I have this right, four out of five patients with advanced cancer though get no benefit from the drugs or minimal benefit of the drugs. Is that accurate?

Thomas Gajewski: Yeah, so in melanoma, about 30 to 50% do have benefit depending on the drug regimen. And so we’ve actually crossed a threshold where in my patient population that I care for, when I started 30 years ago, essentially no patients survived with the standard therapy back then. So now with immunotherapy and with some other additional discoveries that have led to other therapeutic advances, more than half of our patients with metastatic disease have durable clinical benefit.

Paul Rand: For those 50% or so that they’re not getting a benefit, how do you tell them why their body is not responding the way you hoped it would?

Thomas Gajewski: Yeah, so that’s the next level nut to crack. This is where most of our research effort is invested. So most of the treatment failures are in patients who have this cold tumor phenotype, meaning that the good immune cells have not been allowed to enter the tumor microenvironment. And so if they’re not there, they can’t do their work of recognizing and killing tumor cells. And so we’ve spent a lot of time thinking about that the last 10 or more years, 12 years. And one of the things that has enabled a deeper study of this is by studying actual patients. So we initiated more than 10 years ago, we call it a biobanking program. So biobanking from patient material. And what we envisioned, sort of a thought experiment, two patients could be different in multiple dimensions, two cancer patients. They could be different because their cancer cells are different.

So maybe there are different mutations in the cancer cells that make some of them susceptible to the immune response and some of them not susceptible. So we can collect the tumors from patients and do sophisticated analyses on them and see if there are any patterns, responders, non-responders. So that’s category number one. Category number two is that the patient could be different. Patients are different. We have a different collection of inherited genes that we inherit from our patients, and we know that there are variants in inherited genes connected to autoimmunity, autoimmune diseases like rheumatoid arthritis or lupus. And so we view this anti-tumor immune response that happens on its own kind of like an autoimmune reaction. So maybe it’s similar to autoimmunity. So we decided we could bank their germline DNA, their inherited genes from blood cells, and then sequence their inherited genes and see if there are any patterns.

That was a second category. This third category was environmental, and it’s hard to scientifically analyze everything about an individual’s environment. It’s too complex, it’s not quantitative, but there’s a component of environment that we realized we could measure, which is the composition of bacteria in the gut. And this is called the gut microbiome. And when we started this, there was a field emerging demonstrating that the composition of bacteria in the GI tract in the gut can regulate the whole immune response in the host. And so we thought we should start measuring that too because it’s measurable. We can take a stool sample, we can do sequencing of the gut bacteria and figure out what they are. So through biobanking, we have over a thousand patients with different cancers getting immunotherapies now biobanked. We have this collection of samples. And so we could analyze the tumor by gene sequencing, we can analyze the patient by gene sequencing, and we could analyze the gut microbiome by gene sequencing.

And it turns out each one of these dimensions is important and has given new insights.

Paul Rand: So before you start or think about starting a treatment, are you able to tell whether the patient is going to end up being hot or cold?

Thomas Gajewski: So we can do that in an experimental test. There isn’t a clinically approved test, although it’s doable, and I’m not sure why some of these cancer genomics companies have not done this, but we have a platform that’s called RNA sequencing, where you can sequence all of the genes in the tumor that are expressed in the tumor. And it turns out that’s a pretty good predictor of whether a patient’s going to respond to our current immunotherapy.

Paul Rand: You talked a second ago, you were talking about the gut microbiome, and you’ve done a study where you had a couple of groups of mice fighting cancers at different rates. And the only difference, if I recall this correctly, was the bacteria in their guts.

Thomas Gajewski: Yeah, that’s true. When we started entertaining this notion that maybe the gut microbiome could be important, we started banking the stool samples from patients, but that took time. It took a couple of years to get those samples. In the meantime, we had a mouse model. And I’m sure the vast majority of people don’t know how these mouse experiments are done. There are companies that breed mice that are genetically identical and they breed them in a facility and we buy them and they’re shipped under sterile conditions and they enter our facility and we do our experiments to try and study the immune response against cancer. It turns out there are different vendors where you can buy these mice and the price is different. And sometimes the price goes down in another vendor, so you switch vendors. And what happened is the experimental results weren’t the same. It’s the same breed of mouse, but the immunotherapy was working better in mice from one vendor than the other vendor. And so we thought it’s the same genetic mice. They’re just being bred in these different facilities. Maybe it’s the microbiome that’s different because it’s something. So then we did all these experiments and we found all the difference was attributed to the microbiome.

Paul Rand: Amazing.

Thomas Gajewski: Amazing. And the mice that were responding poorly, we could treat them by giving a fecal transplant from the good mice into the bad mice. And then the bad mice responded again. Remarkable. Remarkable. Transferring the bacteria from the stool of the good mice. And then we did sequencing and culturing. We identified some good bacteria, and one of them is a strain of bacteria. It’s called bifidobacterium. And we found an isolated bifidobacterium that we could give to the mice and it became a drug. It became a therapeutic against their tumor and then made the immunotherapy work better. So that was super exciting and totally possible to translate to the clinic.

Paul Rand: Okay. Well, so you did find, speaking of that, the same pattern in people. Is that right? And so you had stool samples from melanoma patients, and that’s telling you some things as well.

Thomas Gajewski: That’s exactly right. So we have responders and non-responders, which are to immunotherapy, the anti-PD-1 immunotherapy drug, which largely clusters with hot and cold tumors. And we sequenced the gut bacteria, and we found that there were bacteria enriched in the responder patients, then also other bacteria enriched in the non-responder patients. And it turns out both of those are important. But among the bacteria enriched in the responder patients were some bifidobacteria strains like we had found in the mice. And so what we did to prove causality, I told you about these fecal transfer experiments in mice. We took the patient stool samples, took the bacteria, and gave a fecal transplant to the mice. And from responder patients, we found there were samples that could improve efficacy in the mice. And then from the non-responders, it didn’t work. And so that proved there could be a causal mechanism based on the gut microbiome in the patients, not just a correlation that just happened to correlate with their immunotherapy efficacy.

Paul Rand: Okay. And so I guess the question, does this change or should it change the way that I’m eating? And especially if I’m being treated for cancer, do I need to be thinking I should be eating more fermented foods, for example?

Thomas Gajewski: Yeah, it’s super interesting. So it’s completely opened up this new direction. We’re working on each of these directions as a therapeutic opportunity, and we want to reproduce or give the effects of the good bacteria, the ones that are in the patients who are responders. So there are three main ways to do it, and we call them prebiotics, probiotics, or postbiotics. So prebiotics, that’s basically food for the good bacteria.

If you feed them, they expand, they dominate, they kind of take over the niches in the gut, and then they do their thing to make your immune system healthier. And then patients who eat a high fiber diet, which means fruits and vegetables, complex grains, beans, that sort of thing, they do better. So fiber and Mediterranean diet, which is also a lot of fiber, these are the things that we know so far. Then another thing is that we made an accidental discovery. There’s a drug that, I won’t mention the name of it, but it’s a drug that’s used for another purpose in the clinic. We found that it also is food for bifidobacterium. It’s a prebiotic. And so we actually just started a new clinical trial where we give this drug as a prebiotic to see if we can improve immunotherapy efficacy in patients.

And it’s a cheap drug. We’re repurposing it. If you think that these cancer immunotherapies are $20,000 a dose or something like that, this drug would be like $30 a dose. So if it works, it’s going to be really interesting. But it has opened up this field of creating the right probiotic. So in other words, putting the good bacteria back into the patient. So at University of Chicago, we have the Duchossois Family Institute, which was a major donation to build essentially a microbiome center. And Eric Pamer has been the director of that facility, and he used some of the infrastructure monies to create a manufacturing facility to make our own live bacterial therapeutics, meaning probiotics, on campus in an FDA compliant and inspected way. And so a bunch of strange bacteria have already been characterized, quality controlled, and packaged in capsules. And we’re working on the next series in our group.

And very soon we’ll be able to give to patients what we think are the good bacteria. 

Paul Rand: That’s Incredible. 

Thomas Gajewski: Not just an over-the-counter probiotic of some random bacteria that might do something, but the ones that we’ve confirmed scientifically in the laboratory to improve cancer immunotherapy efficacy. Then the new future is postbiotics. We’re figuring out how those good bacteria work. Stay tuned over the next five years. 

Paul Rand: Very exciting work. As I’m listening to you talk, it does sound like a lot of this is traced back to the genes that people are born with. And so I’m wondering, is one person’s immune system simply just better able genetically to fight cancer than somebody else’s?

Thomas Gajewski: Yeah, that’s a really important question. And I mentioned that that was the third dimension that we were measuring in patients.

Paul Rand: Yeah. Okay.

Thomas Gajewski: And so the concept here that we were entertaining was that maybe there are variants in genes you’re born with that make your immune system a little bit more trigger happy. And in certain contexts that might lead to an autoimmune disease. But in the cancer context, it could mean you’re more likely to respond to immunotherapy because your immune system is a little bit more trigger happy. So it turns out to be true.

In my group, and we have an expanded group of investigators in the world now working on identifying these gene variants, there are sets of genes, many of which are autoimmune genes that are enriched in patients who respond to the immunotherapy drugs. And this might be a little bit hard to explain. What we’re looking for is loss of function variants, reduced function variants. What I mean by that is let’s say there’s an enzyme that normally does a job in an immune cell. And if there’s a mutation in that gene, the enzyme works less well and you get autoimmunity or you get better immune control by immunotherapy of your cancer. The reason we’re looking for loss of function genes is because let’s say that loss of function mutation is present in 10% of the patients, but in the rest of the patients it’s a normal gene. We can drug, if we develop a drug that mimics that loss of function, then we can give that to the other 90% of patients and put them on the same playing field as the patients who were born with that variant.

Paul Rand: Interesting.

Thomas Gajewski: So that was the theory. And in the field and in my group, we’ve identified a collection of these. And the way we test them if they’re candidate drug targets is we make genetically engineered mice that are missing that enzyme. We see if their antitumor immune response is improved. We figure out how it works. And then we now have a medicinal chemistry collaboration where we’re working with chemists to develop drugs, small molecule drugs that ultimately could be pills that a patient would take to mimic what that gene variant did in the rare individuals and reduce the function of that enzyme and then see if now you have an immunotherapy drug by learning from these genetic variants from the rare patients. You follow me?

Paul Rand: Wow, I do.

Thomas Gajewski: Yeah, yeah. And so that’s the next frontier that we’re working on that could become the next biotech startup company through our Polsky Center for Entrepreneurship and Innovation. We’ve been successful so far having two co-founded two biotech spinoffs out of work done in the group. And we’re hoping this is going to be a new category of immunotherapy drugs, small molecules against these intracellular targets.

Paul Rand: Talk a little more future-oriented, and maybe going out maybe five years in terms of the field you’re working in right now, what do you expect to be different? And let’s go all the way 20 years out. And does chemotherapy even still exist in 20 years because of the advances that are being made?

Thomas Gajewski: In the immunotherapy world, we have settings where we don’t use any chemotherapy anymore. We don’t use any radiation therapy anymore. In melanoma, that’s the case. In some other cancers, chemotherapy has become replaced by immune-targeted chemotherapy. So there was just a major publication in bladder cancer, another cancer type that’s responsive to immunotherapy, where an ADZ plus immunotherapy was better than chemotherapy. So chemotherapy’s probably going to go away. 

Paul Rand: I bet a lot of people are probably excited to hear that.

Thomas Gajewski: Yeah, you could imagine a future in many cancers where even chemotherapy as we know it will go away, will be used less and less often because we can better and better target the chemotherapy to the tumor or the tumor microenvironment. If you just get it in the vicinity of the tumor, that can be efficacious also. So I can envision a world where we’re infrequently using chemotherapy so long as we’ve made all the right discoveries so we can accomplish these things. We can make immunotherapy work or we can successfully target chemotherapy to the tumor, or with those antibodies, we can successfully target T-cells to the tumor. Those are called bispecific antibodies, T-cell engagers. So we have drugs where we target the tumor, and then there’s another arm of the drug that brings the immune cells in when they’re not there normally. And those are efficacious and approved in some cancers.

So even when it’s not immunotherapy, as we’ve been talking about it, in my air quotes, the immune molecules like antibodies are being used to bring drugs or cells, immune cells, into the tumor site with clinical benefit, tumor shrinkage, and with FDA approvals. So I think that’s a reasonable idea that chemotherapy as we know it is going to be used less and less.