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Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of Urologic Oncology at MD Anderson Cancer Center. Joining us today is Professor Sumanta Pal or Monty as we all know him, who's professor and vice chair of Academic Affairs in the Department of Medical Oncology and Experimental Therapeutics at City of Hope Comprehensive Cancer Center. Monty is a dear friend, an expert in all things that come to GU cancers and has a broad knowledge of cancer and immunology in general, and gave this really excellent summary of the impact of the microbiome on GU cancers and immunotherapy at a recent SUO meeting that everyone was enthralled by. Monty, thank you for taking the time and joining us today, and sharing this knowledge and wisdom with a broader audience.

Sumanta Kumar Pal: Oh, you got it, Ashish. Thanks so much for having me. It was a really fun opportunity to present this broad overview of the impact of the microbiome on immunotherapy to the SUO audience. And as I'll conclude with, I think there's a lot of investigators in our space who actually share my fascination with the microbiome and its relationship to treatment outcomes. Having said that, I wish I could give credit to initial explorations in this disease to our GU colleagues. But in fact, the first forays in looking at this were in melanoma and lung cancer. There were three papers that were published in Science back in January 2018, and all of these three papers linked the outcome of PD-1 inhibition to the composition of the gut microbiome. Now, I'll point out here that there are a couple of differences amongst these papers. They did look at different diseases.

The first paper was focused on melanoma. The second, primarily on lung, also a smidgen on kidney cancer. The third on melanoma. But what's really important to bear in mind here is that each one of these three papers actually suggested a different bacterium could be associated with immunotherapy response. So a common theme of the microbiome impacting outcome, but differing suggestions regarding how the microbiome was impacted. I'm going to cite a lot, my dear friend and colleague Bertrand Routy, who's at the University of Montreal. He actually led the investigation that focused on lung cancer and kidney cancer that I'd highlighted on the previous slide. And this is really just to show you a snippet of what this data ultimately looks like. So this was a cohort of 60 non-small cell lung cancer patients, 40 renal cell patients with blood and stool collected at serial time points.

And I think we're used to seeing heat maps of genes that might be associated with outcome. Here, what's pretty fascinating is that if you look on the right-hand side of my slide, there are specific bacterial species that seem to be really tethered to whether or not a patient responds as in green or doesn't respond as in red. So we can slowly start to gather a heat map, if you will, of various bacteria that are implicated in their immunotherapy response. Our group did something similar. This is a paper that we published in European Urology that focused on 31 patients with renal cell carcinoma. We followed stool collection serially during the course of treatment. And one of the things that we found, and this is actually a common theme across the literature, is that beyond a specific bacterium being associated with response, it may actually be the extent of diversity in the microbiome that's tethered to response as well. And that was one of the key findings of this paper.

Ours is also one of the first to really sort of look serially at collections of stool over the course of time. And there definitely seemed to be some temporal changes in microbiome composition as you'd expect in patients receiving therapies that change over time, diets that change over time, etc. Now, this particular paper, I think, has caused a lot of pause in our clinical practices. This is led by my dear friend Lisa Derosa, who's at Gustave Roussy in Paris. But she looked at a very large cohort of renal cell, non-small cell patients and really, identified that antibiotics could potentially be linked to the response to checkpoint inhibitors. And this is maybe a demonstration that if you're modulating the microbiome through the use of oral antibiotics, you might potentially impact outcomes. You can see here that if patients with renal cell, this is specifically teasing out that renal cell cohort received antibiotic therapy, they really had a stunted response to therapy. About 64% had primary progressive disease, meaning that their tumors grew right through immune treatment.

If on the other hand, they hadn't received antibiotic therapy, that primary progressive disease rate was only 20%. Now, I wanted to discuss some of the techniques that we're using to take this to the next level and really modulate the gut microbiome. Probably one of the most exciting forays is fecal microbiome transplant. This is exactly as it sounds, taking donor feces, blending them together, filtering it, and then delivering it to patients either through endoscopies, that is direct delivery of stool into the lower gut, or through oral capsules. These oral capsule formulations are fascinating. There are different ways to actually get them through the various pH environments of the stomach and lower gut. In any case, there are two very prominent ways in which we can populate the gut microbiome with someone else's microbiome.

This was first looked at by my colleagues again in melanoma, Diwakar Davar and Baruch led the first two studies published in Science. What's fascinating here is that patients who have primary progression on PD-1 inhibitors, meaning growth right through, when rechallenged with a PD-1 inhibitor plus FMT from a responder, were actually able to achieve responses, not in every case, but in about 30% of cases. You can see here that there's a handful of individuals who have reductions in tumor size following the use of fecal microbiome transplant. It also seems, and this is probably implicit, it matters in bone marrow transplant and other fields, that the composition of the donor is really critical here. In this second study that was also published in Science, patients were rechallenged with PD-1 inhibition from responding patients. It actually seemed as though the nature of the responder was important. You can see that patients who received stool from donor one responded better than patients who received stool from donor two.

Bertrand Routy, again, my dear friend and collaborator, has published this study that looked at healthy donor FMT. So maybe we don't need to go to that rare pool of patients who've had a complete response to immunotherapy, maybe we can actually pull stool from patients who are completely treatment naive and healthy donors, in fact. And that's what this study aimed to do. It showed that if you use stool from healthy donors, you can really exact major reductions in tumor dimension above and beyond what you'd expect with immunotherapy alone. There are some challenges with FMT. It requires lots of resources. You have to have your GI endoscopy suite set up to do this. It's also challenging to ensure appropriate sourcing of the product, and there are lots of potential safety risks too. It's also really unknown what the optimal FMT donor pool constitutes. Is it a healthy donor? Is it a responding patient? We really don't know at this point. So I would say there are lots of practical and technical challenges to this, and commercialization, obviously, is a huge hurdle.

So what we've really taken to in our group is taking a simpler approach, and this is something that can be applied across all GU malignancies and hopefully, all settings in which IO is relevant in general. We've identified a bacterial species, Clostridium butyricum, that's actually available in an oral spore formulation in Japan. When ingested, this particular bacterium heads into the lower gut, repopulates, and increases the production of Bifidobacterial species, which we think is associated with a favorable response. Now, that's the simple way in which this works. We actually think that there are lots of complex mechanisms in which various T cells are modified, such as gamma delta T cells, CD4 cells, etc., to really change the immune milieu around the tumor. Having said that, at least in our theoretical construct over here, it's easier to think that this continuum really increases favorable bacterial species in the gut and increases T-cell activation.

My group has led a number of studies. My terrific fellows, Nazli Dizman and Hedyeh Ebrahimi, have led these two that were first published in Nature Medicine and then more recently presented at ASCO 2023, in which we've taken contemporary regimens for renal cell carcinoma. In this case, Nivo/Ipi. In the case of the second study, Cabo/Nivo and randomized patients to receive these regimens with or without CBM588, this Clostridium butyricum spore. Now, at first blush, these are very small studies. But I will say the clinical data has been very compelling. We saw a benefit in terms of progression-free survival across these two studies, and also a significant benefit in response. It was clear to us that patients who had the addition of CBM588 in both of these studies seemed to have an enhanced response to their immunotherapy-based regimens. So where is this going? Ulka Vaishampayan, who also presented at the SUO meeting, as well as Pedro Barata, are developing a study that is going to be looking at this in a definitive fashion, in a phase three fashion. Patients will receive conventional immunotherapy regimens with or without CBM588.

So, really looking forward to definitive proof that this works. I'm looking at anything and everything in my group. My colleague, Bertrand Routy, had suggested that Camu camu, which is a natural product that derives from a fruit in South America, may potentially enhance outcomes of immunotherapy; that was based on preclinical models. We now actually have a study that's being run by Regina Barragan-Carillo, one of my outstanding fellows from Mexico City, that's going to be looking at Nivo/Ipi with or without Camu camu. And just so you're not thinking this is something way out in left field, the group in Montreal has actually published two patients, two case reports of patients who were rechallenged with immunotherapy with Camu camu and actually derived complete or partial responses to therapy, which I think is fascinating. So there's some suggestion that this may work in other diseases.

Now, what I've cited here is primarily work that's coming from my group, but there's a lot that's happening in the GU space. Laura Bukavina is doing some really great work that pertains to early detection of bladder cancer using the microbiome. Mike Liss has done some great work looking at pathologic features in RCC with the intratumoral microbiome. These are actually elements of the microbiome that are present within tumors. And Nima Sharifi, who's now in Miami, again, has done some really great work in prostate cancer, looking at microbiome metabolites that are associated with prostate cancer risk. So, just a snippet of the research that's ongoing within the field. And I think that you would agree that there's a lot of exciting work in this space. So, Ashish, I'll turn it back over to you.

Ashish Kamat: Thanks so much, Monty. That was an excellent overview of the importance of the microbiome in cancers in general and the evolution. Let me see if I can pick your brain a little bit because I know you've done a deep dive into this. Right? We often, over the last three decades that both of us have been in the field, seen things come and go and become vogue and everybody's sort of interested in this. And that's pretty much what the perception of the microbiome was when it first burst on the scene, right? Because people were looking at bacteria, they were looking at, like you said, small snippets of patients. With the current data that we have and the ability to do a wide cast, it's obvious to me at least, and correct me if I'm wrong, that it's not a particular bacteria. I mean, you showed it with C butyricum. But it seems to be an amalgam of the right microbiome. What are your thoughts on that?

Sumanta Kumar Pal: I couldn't agree with you more. And the intent of CBM588 Clostridium butyricum is really to sort of generate this milieu of gut bacteria that are favorable to immunotherapy response. I think that the approaches that I've described are really at opposite ends of the spectrum. With fecal microbiome transplant, you're getting any and every bug that's entailed in someone else's successful "microbiome." With CBM588, you're focusing on one particular species. But there are some companies that we're working with now that are actually developing consortia of bacteria, maybe eight or nine bacteria that may potentially predict response. We're trying to see whether or not therapeutic administration of those bacteria can actually enhance response now.

Ashish Kamat: Yeah. And it's interesting because if you look at the Clostridium butyricum, it's been used in agriculture and in animal farming for many, many years. Right? And there was some evidence that it helped animals become more robust and produce more milk, et cetera. And of course, now, we're using it in humans. It's almost like it's the circle of life in some ways. Are you alluded a little bit to Camu camu. Is that also related to the microbiome? Because I know that's been purported to have a very high concentration of vitamin C and other beneficial compounds. Is that a pure microbiome thing or do you think it synergizes with the gut bacteria?

Sumanta Kumar Pal: Yeah. So actually, the primary endpoint in that particular study is to look for changes in ruminococcus species. And that's really predicated on preclinical work done in mouse models suggesting that ingestion of Camu camu really leads to a higher abundance of ruminococcus and that's the purported way in which we think that that's actually enhancing IO-based outcomes.

Ashish Kamat: A couple of practical points 'cause our audience is not just physicians, but sometimes patients that are looking to get educated. And we'll often now have patients that come to clinic and they hear about this microbiome, it's very important when it comes to cancer responses and they want to modulate their own microbiome by going out to the vitamin shop or somewhere and getting these probiotics. What do you advise your patients when they ask you, "Hey, Dr. Pal, is there something I can do right now to help myself?"

Sumanta Kumar Pal: Yeah, it's a great question. And I'll tell you that the data is really all over the place when it comes to how probiotics might impact outcome. But perhaps, the best publication that I could refer to is from the MD Anderson Group. Jennifer Wargo had a really nice paper in Science, the first author is Christine Spencer. And it looks at the outcome of patients who are taking probiotics, and it also dissects to some extent their dietary composition. But what was really intriguing is that in this cohort of patients with advanced melanoma who were receiving checkpoint inhibitors, taking standard over the counter probiotics actually seemed to impede outcome. So I think there's no way to really devise a regimen of probiotics that will augment IO-based therapies. The only way forward at this point in time in 2024 is through participation in clinical trials.

Ashish Kamat: Yeah. And again, I didn't set you up to refer to Jen's study, but that was what I had at the back of my mind. Because it's hard sometimes to tell a patient you have to enroll in a clinical trial and then at the same time, they've read about all these advertisements and other things that get thrown out saying, do this, do that. Last question along these lines for you, are you today advising patients to stay off antibiotics? 'Cause that's another question that we often get. Not if they have a flaring infection and they absolutely need it, but if it's a mild UTI, for example, during therapy, have you changed your practice in how quickly you recommend antibiotics or how quickly you ask them to come off any antibiotics they might be on during concurrent therapy?

Sumanta Kumar Pal: Absolutely. I mean, when I think about converting my practice from an internal medicine practice during residency to an oncology practice as a fellow, I probably got more aggressive about the use of antibiotics in general, right? It's a sicker population, you worry about the consequences of any intercurrent illness. But what I will say is that all the data that's emerging right now has really induced some pause. So I really don't bring out that prescription pad for sinusitis anymore or I'll really try to get around prescribing antibiotics for infections. Unless, as you alluded to, it's absolutely necessary. I definitely think that it's changed my practice in a manner that's far more conservative around antibiotics.

Ashish Kamat: Yeah, great point. And I just want to emphasize that Curtis Nickel, who did a lot of work when it comes to GU cancers and it wasn't called the microbiome then, but essentially, all of his work in the '90s and early 2000s would always stress that. You don't need to kill all the bacteria, you just need to kill the ones that are going to potentially kill your patient. Right? And sometimes we forget that and we over treat, but I think that's a great point. Monty, once again, thank you so much for taking the time and spending it with us. It's really appreciated. And thank you to UroToday for hosting us.

Sumanta Kumar Pal: Thank you very much.