Dr. Mike Smith (Host): This is Pediatric Insights: Advances and Innovations with Children's Health, where we explore the latest in pediatric care and research. I'm your host, Dr. Mike. And today, we'll discuss the National Institutes of Health-funded research on how Candida colonization impacts cancer development and treatment outcomes.

With us today is Dr. Andrew Koh. He's Chief of the Division of Pediatric Hematology and Oncology at UT Southwestern and Medical Director of the Pauline Gill Center for Cancer and Blood Disorders at Children's Health. Dr. Koh, thanks for joining us today.

Dr. Andy Koh: My pleasure. I'm glad to be here.

Host: So, can you give us an overview of your NIH-funded research and what really inspired you to study Candida and ultimately that potential connection to cancer?

Dr. Andy Koh: Yeah. So, the story goes back 20 years. You know, I'd actually done no science whatsoever, and I was a third-year clinical fellow out of a four-year fellowship, and I picked up a pipette for the first time. And I was trying to understand why cancer and stem cell transplant patients can get these terrible life-threatening bacterial and fungal infections that ironically come from the patient themselves. So, they're not catching these bugs from the outside. They're coming from the inside and spreading into the bloodstream and causing infections, and this was before there was this huge interest in the gut microbiome. So. I was really trying to understand how bacteria and fungi can colonize your gastrointestinal tract and what were the factors that dictated whether these bugs, what we call translocators, move outside of the gut and into the bloodstream.

So, that led to like a 20-year venture into these basic questions and the gut microbiome, which are the trillions of microorganisms that reside within our gut. So in fact, human beings are outnumbered by bacterial cells by a factor of 10 to a hundred to one. So, we're actually more bacteria than we are human. You know, now, there's this wealth of information, including from our own group, that there's certain bugs that are beneficial that promote health, and there's certain bugs that actually can cause disease. And so, we've been trying to understand that balance, trying to understand how bacteria, the good guy bugs can help educate your immune system and activate them in the control of infections, also in the role of autoimmunity and also in the role of anti-tumor immunity.

So, we stumbled upon Candida, because Candida albicans is the most common human commensal, which is a bug that resides harmlessly in your gut and sometimes provides benefit, but it can also become the biggest pathogen in human beings. And the major reservoir for Candida albicans is the human gastrointestinal tract. So, most of us, particularly those who live in western societies and eat western kind of diets are colonized with Candida albicans. And so, we've been trying to understand for the last almost 25 years what is it about certain Candida strains that give them the ability to cause infections? What is it about a healthy microbiome that prevents them? And what are the factors that we could potentially leverage in a therapeutic fashion to prevent these infections?

Host: It is fascinating. The story at the beginning, Dr. Koh, is you literally went through the scientific method of how you came to study Candida in cancer. This is fantastic. And of course, the microbiome today is receiving a lot of attention. A lot of research going into it. We're learning it connects to the liver, has influence on the gut, can even have influence on the brain. It's fascinating. So, is that where you're focusing now, is really that the microbiome, the Candida, and cancer connection? Is that the focus now for your research?

Dr. Andy Koh: Well, interestingly, we were studying primarily how Candida causes infections in cancer and stem cell transplant patients. And then, in the last seven or eight years, we took a little bit of a detour because what ended up happening was the head of the experimental therapeutics program at our cancer center wanted us to do some microbiome profiling or sequencing on melanoma, melanoma is a skin cancer, so patients with melanoma who are getting a novel form, this is seven, eight, nine, 10 years ago of immunotherapy called checkpoint blockade. And what this has now afforded us is by basically administration of these checkpoint blockade antibodies, you can now get patients with previously incurable cancers into remission for five years and ongoing.

So interestingly, in 2015, two papers came out in a premier scientific journal called Science that showed in mouse models of cancer, if the mice didn't have microbiomes, meaning they were germ free, or if you treated these mice with antibiotics, that they didn't respond to this cancer immunotherapy. So, we were one of the first five or six groups in the world in 2017 to show that indeed patients who responded favorably to this cancer immunotherapy had a completely different set of bacteria in their gut than those who did not. We were able to get an NCI R01 and work with Merck and Novartis. And we basically landed upon a couple of very common and prevalent commensal bacteria that are associated with response to cancer immunotherapy. And in our hands, we can use it as a therapy to enhance the efficacy of these cancer immunotherapy. So, that led us into the bacterial microbiome, cancer immunotherapy things. And now, we're kind of coming full circle and wondering now how does Candida play a role in promoting or maybe preventing anti-cancer, anti-tumor immunity? So, that's essentially what we're doing now with the Candida infection side and also from the anti-tumor side.

Host: So, does that mean if you have a patient who doesn't have these specific strains, and they're about to go into this immunotherapy, that you can actually replenish them or give them these strains in a probiotic product or something and then put them into the therapy? 

Dr. Andy Koh: So, that's the thought, you know? Exactly. If you identify patients that have an absence of these beneficial bacteria, could you put them "back into their gut" through a probiotic and do it? Now, that's the thought. And in mice, it seems like we and other groups can do it. The problem is, unfortunately, it hasn't been successful in humans, and I think that's for a number of reasons. You know, when we have mice that we experiment on, we control all their variables, right? We control when they sleep, what they eat, et cetera. Human beings aren't so easy, Let's say you go out on a night of binge drinking because they got just a promotion or they got good news or they have some fast food, then, you know, all that hard work that you and the patient did to establish those good guy bugs in your gut could get eradicated, right?

So, our group has arrived on a novel form, an injectable form of bugs because then as you had mentioned, the thought would be when you go in and get your cancer immunotherapy, you get these beneficial bugs to kind of ramp up your immune system so that you're most optimized to get the maximum benefit from these immunotherapies.

Host: That's amazing. I love that. For the lay audience, can you give us just real quick, what's the connection between some of these healthy bacterial strains and the immune system? How exactly does having a nice, diverse microbiome really help my immune system? What's going on there?

Dr. Andy Koh: Yeah. So, what's interesting is when you're born, your microbiome is relatively "empty", clean, and you acquire these organisms that basically help your immune system get educated. And by education, it's two things. You know, you basically educate your immune system to be aware of potentially bad or harmful bugs. So, you can get the defense systems going up, and you also train your immune system not to overreact to all the potential stimuli that we get, because we're constantly exposed to different dietary stimuli, microorganisms, et cetera, et cetera.

And so, our thought is that if you use pathogenic bacteria, I mean these are bacteria that cause diseases, while they can ramp up the inflammation-- and inflammation is actually good in this context because it helps you fight and kill cancer cells-- that it may be too much and it may drive the patient to what we call like sepsis-like physiology, which is essentially what happens when a patient gets a terrible, overwhelming bacterial infection. And the converse, if you don't stimulate the immune system in that way, then it may not be sufficient to really promote the anti-cancer. So, you use a Goldilocks metaphor, I think what we've arrived at is these commensal bacteria stimulate your immune system enough, but not overboard so that this helps you fight the cancer in a beneficial way.

Host: So, it sounds like what you just kind of described with the inflammatory component, if you get too much, is that what we hear in the media and stuff about cytokine storm? Is that kind of what you're talking about?

Dr. Andy Koh: Exactly. And some of these other forms of cancer immunotherapy, something called CAR T-cells, which the fancy word is chimeric antigen receptor T-cell. But really, that's a fancy word for saying I take somebody's white blood cell. And I genetically engineer it so that it can recognize a cancer tumor target. And then, you re-inject it back into the patient. And it's almost like a heat-seeking missile. But instead of going after heat, it goes after tumors, right? And one of the side effects, as you mentioned, is the cytokine storm, where too many pro-inflammatory proteins are produced. So again, it's good to have inflammation because you kill the cancer cells, but you don't want to do it at the harm of the patient. So, it's kind of doing that fine balance, which is really the trick right now.

Host: Okay. So, you've been doing this research for quite some time, you said 20 years, I think, right? So, 20 years of all of this. What's the most surprising thing you've come across so far, most surprising finding?

Dr. Andy Koh: I think it was this recent discovery that certain bacteria could help you fight against cancer, but not push you into what we call sepsis. So, this idea of using bacteria to treat cancer is actually a pretty old one. So, there was an American surgeon in the late 1890s, early 1900s. His name is William Koley. And he observed that a patient who had some sort of oral oropharyngeal cancer got like a skin infection with something called Streptococcus pyogenes. That's that flesh-eating strep you can hear in headlines in the National Enquirer. And that patient, while they got that infection, the cancer spontaneously resolved. It just shrunk and just basically disappeared. So, he started giving a mixture of a very potent mixture of two types of pathogenic or disease-causing bacteria in a heat-killed form. And it was affectionately known as Koley's toxin. And so, William Koley is considered the father of cancer immunotherapy.

I have an article from 1908 in the New York Times that I show in my talks and how he was giving Koley's toxin. Koley's toxin was given up until 1950, right before the advent of regular cytotoxic chemotherapy, right? So, again, I think what we're realizing is the immune system is finely tuned to recognize bugs that are pathogenic versus those are commensal. And can you leverage that in a way, kind of dial in the right amount of inflammation to really help the patient fight cancer, but not get so sick that they end up in the ICU intubated and on pressors and et cetera?

Host: Fascinating, right? So, the idea of using the patient's own immune system goes way back even before chemotherapy. And now, it's coming back because we realize it is probably the most powerful weapon we have.

Dr. Andy Koh: Well, and the other beautiful thing is, you know, if you think about it crudely, the mainstay of cancer therapy for the last 60 years have essentially been poisons that kill cancer cells better than they kill regular cells. But in some cases, I mean, that's why your hair falls out and that's why you get ulcers in your mouth and stuff like that. And you know, we write a fine line by giving just enough chemo to kill the cancer cell, but not kill the patient. But even nonetheless, there's a lot of collateral damage, and our patients get lots of side effects. So, why not use the immune system whose whole job is to do what? Kill and attack things that shouldn't be in your body, that not only include microorganisms, but also include cancer cells. Cancer cells are not normal. They're the enemy. They're the ones that are also targeted by the immune system to be basically targeted and removed.

Host: How is all this going to impact patient care and treatment strategies really now and over the next decades? I mean, where do you see this going? And if you could predict any type of outcome as we hone in on this immunotherapy microbiome, what do you think?

Dr. Andy Koh: Yeah. I mean, I think it goes in conjunction with this idea of precision medicine and the idea that immunotherapy is actually here to stay. I mean, for the longest time, before like these CAR T-cells and the checkpoint blockade, it was always this kind of unfulfilled promise. Yeah, right, we're going to be able to harness the immune system with some other tumor vaccine that didn't work. But in the last 15 years or so, it's here to stay and now you're seeing elements of cancer immunotherapy in the frontline therapy, in combination with many different therapies.

And so, what I think we're beginning to understand is cancer is so complex and hard to treat that we have to use many different tools in our armamentarium to treat it properly. And so, I think immunotherapy is now just part of the normal armamentarium. And as we get a better understanding and get more tools, it's very exciting because the side effects tend to be less pronounced than with the regular cytotoxic chemotherapy.

Host: So obviously, your research has led to a lot of new medical insights, and it's fascinating. I could talk for a long time with you, Dr. Koh, about this. But what's your next step? Where are you now taking this?

Dr. Andy Koh: This immune checkpoint blockade, while it's done wonders for adult cancers, is largely ineffective in pediatric cancers. And so while I've been doing research on adult cancers, you know, I am a pediatric oncologist. And I run our Pediatric-Oncology, Hematology-Oncology division. So, we're trying to figure out ways to understand why doesn't the checkpoint blockade work in pediatric solid tumors like Ewing sarcoma or rhabdomyosarcoma, and is it somehow linked to the microbiota?

So, this is the irony. I've been a clinical oncologist for over 20 years, but we've only really started studying pediatric cancer in my lab in the last three or four years. We're really trying to leverage what we've learned on the adult side to see if we can apply it on the pediatric side.

Host: Awesome stuff. So given everything we just laid out, everything you just talked about, the Candida stuff, the microbiome, almost like the personalized approach to this using the immune system. Is there anything else you'd like the listening audience to know?

Dr. Andy Koh: There's a lot of noise out there now about the microbiome, both, you know, in the lay press and scientifically. And so, I think one thing we can say for sure is the microbiome is really important for your obviously immune education and responses and for your metabolism. And, you know, when folks ask me about over-the-counter probiotics and diet and this or that, we're not quite ready for prime time for precision shaping or modulating of the microbiome. But if folks ask me, what can I do? And again, this is harder to do than to say, is just to eat a good, healthy diet. It's probably the best thing for your microbiome, which means, again, I know it's hard. Don't eat, you know, processed foods, and anything that tastes really good, probably try to avoid, right? All in moderation. All those things. Like, you know, if you were to imagine that as human beings, we were still kind of hunter-gatherers and what are the things you'd eat? You'd eat fruits and berries and nuts Again, harder to do than to say, but that's the kind of common sense advice I would give.

Host: Fantastic. Dr. Koh, this has been a wonderful conversation. Thank you so much for your time with us today and for coming on the show.

Dr. Andy Koh: Thank you so much for having me. I appreciate it.

Host: I want to say thank you to our audience as well for listening to Pediatric Insights, advances in Innovations with Children's Health, where we explore the latest in pediatric care and research. You can find more information at children.com. And if you found this podcast helpful, please rate and review it or share the episode. Don't forget to follow Children's Health on your social media channels. I'm Dr. Mike. Thanks for listening.