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Ashish Kamat: Hello, everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. It's a distinct pleasure to welcome to our forum once again, Professor Monty Pal, who's Vice Chair of Academic Affairs at the City of Hope. Monty, thank you for taking the time to once again join us, update us. You spent some time with us previously. The audience internationally really loved hearing what you had to say about the microbiome. In general with cancers, obviously, your focus is kidney cancer and really looking forward to what you have to say and teach us about it in an updated forum. So thanks again and the stage is yours.

Sumanta Kumar Pal: Oh, thanks a lot Ashish, and it's wonderful to be here. I think since our last conversation, the field of the microbiome—and I'll really focus my discussion around kidney cancer—has moved from a place where I think we can consider therapeutic interventions to be exploratory to studies that serve as perhaps somewhat confirmatory, by no means at the phase where these studies are definitive. But I definitely think they're moving in the right direction. And that's really the general update that I'll provide today.

I always like to start by giving just a little bit of background regarding why I think this is so critical. There was this triumvirate of papers that was published in Science back in 2018. And when you look at this array of papers, at first it seems fairly homogeneous. The general thesis here, as I state in the bottom, is that there seems to be a link between the composition of the gut microbiome and outcome with PD-1 inhibitors and checkpoint inhibitors in general.

But there is a little bit of heterogeneity here. If you look to the papers that flank my screen, you can see that the disease focus is in melanoma. Those are papers done at MD Anderson and at the University of Chicago, respectively. If you look at the paper in the middle, that focuses on lung and kidney cancer. And you'll notice that all three of the papers identified different bacterial species that appear to be associated with checkpoint inhibitor response. Nonetheless, I think in broad terms, this suggests that there might be a pathway towards manipulating the microbiome and maybe optimizing outcome with checkpoint inhibitors.

There are so many different approaches to this, and I think in the context of a short discussion, as you and I are having, it’s tough to encompass all of them. The approach that we started with was something called fecal microbiome transplant. And if you're at a large academic center, say UCLA or USC—I'm thinking of locations that are here on the West Side of the United States—I would suggest that you typically are going to have facilities to do a fecal microbiome transplant. This is something that's commonly used for severe and refractory Clostridium difficile colitis, for instance, or C. diff colitis.

But it's something that I would say at many specialized cancer centers like City of Hope, we don't necessarily have the infrastructure for. So I've been very interested in using the approach of live bacterial products. So these are, to be fair, not probiotics, which oftentimes can be random pools of bacterial species, but rather specific strains that enter into the body, deposit at varying points within the gut, and then proliferate, and we think exert their effect through that mechanism.

So this is a simple schematic of an agent that I've had a good degree of experience with called Clostridium butyricum 588, or you'll see it referred to in my talk as CBM588. This is a spore bacteria that we think enters into the lower gut, starts proliferating, and releases butyrate and butyrate propionate. These are all short-chain fatty acids, just a couple of carbons each.

And these enter into the circulation. And we think that they have a profound effect, in fact, upon the composition of the remainder of the gut microbiome. So you might see increased proliferation of species like bifido and others that have been positively associated with clinical outcomes with checkpoint inhibitors. In point of fact, there’s a huge variety of mechanisms that are likely at play, as you can see on the right. But again, that's probably a subject for a two- or three-hour talk, not a short update.

Now, what have we done with this? The major update, issues, that I wanted to present to your audience are that we had an initial study that we likely discussed on our last call, looking at nivolumab and ipilimumab. This is a very common frontline regimen that we're using in kidney cancer. Reasonable efficacy, I would say, and great long-term outcomes for some patients. But clearly, there is a large proportion of individuals that don't respond to this therapy.

So my fellow—excuse me, Dr. Nazli Dizman, who's actually now at MD Anderson—ran this trial, which was published in Nature Medicine back in 2022. I'll caveat this by saying that this is a small study. By no means is this meant to be a definitive trial. Just 30 patients were randomized. Folks received nivo/ipi alone or nivo/ipi with CBM588. Thirty patients in total. And a couple of years later, we thought to ourselves, well, gosh, we've got some encouraging data here that I'll share with you in just a moment.

“Why don't we see if other base regimens could be improved by CBM588?” So my current fellow, Dr. Hedyeh Ebrahimi, actually put together this trial looking at cabozantinib and nivolumab. And if you look at the market share of each of these regimens in the US, I would suggest that about a third of patients receive nivo/ipi up front, a third probably receive cabo/nivo, and there's a smattering of other regimens. So with that in mind, we thought that this would just be pragmatic to look at other base regimens that one could use in combination with CBM.

The results across both studies were pretty striking. So in Nazli’s study, we saw that there was a response rate with CBM588 added to nivo/ipi that was more than double what we'd anticipate with nivo/ipi alone based on the small randomization. And when we looked at CBM588 with cabo/nivo—I just want to suggest caution here because the bar graphs are reversed—you can see that with cabo/nivo and CBM588, the benefit there, again, is more than double what we see with cabo/nivo alone. So very encouraging results from these small trials.

And I mentioned at the outset, this is by no means definitive. So I really don't want to encourage patients to start purchasing this over the counter or getting this on Amazon. Right now, this is an agent that's actually distributed widely in Japan. And many of my patients have tried to get a hold of it through that mechanism. I think that most of us listening to this are probably purists and want to see good level 1 evidence. So my dear friend Pedro Barata, who's at Case Western, along with Dr. Ulka Vaishampayan at the University of Michigan, and I are actually putting the study together through SWOG.

And this will be a one-to-one randomization to IO-based therapy. So that could be cabo/nivo, could be nivo/ipi, any other IO-based therapy frontline, plus or minus CBM588. So I think this will be a really important exercise for us to firmly establish whether or not CBM588 has potential. Now, I mentioned that there are other confirmatory data sets that are out there that really suggest that we're on the right track. Before I get to those, I wanted to mention some of the things that we're doing to optimize CBM588.

On the left, my dear friend and junior faculty member, Dr. Alex Chehrazi-Raffle—he's a real up and comer in the field, and he's definitely one to look out for—is using nivo/ipi in a dose escalation trial with CBM588. So this is ongoing now. If you have patients that are interested in CBM588, this is really the avenue that I suggest that they get it, in this really formatted approach. And we're about halfway through this particular dose escalation study. Whatever dose we get here is going to feed into that phase III trial.

And I bet a lot of folks, because I hadn't heard of this, haven't heard of this agent, camu camu. This is a South American berry. And this actually hails from the Amazon. It's actually quite popular among specific subsets of patients, and it’s purported to have these benefits with association with anti-cancer therapy. There's this beautiful paper in Cancer Discovery that came out from my colleagues in Montreal last year that suggests that if you use extracts from camu camu, you can augment the effect of PD-1 inhibition. So my fellow, Dr. Barragan-Carrillo from Mexico City, is actually running this trial at City of Hope, looking at nivo/ipi with or without camu camu.

Now, this really, I think, excited me. This is work that was presented at ESMO just this past October, so literally just a couple of months ahead of us doing this interview today. And this is the so-called TACITO trial. So this uses that other approach that I mentioned to manipulate the microbiome, which is to take a stool from another individual and transplant it into a patient with kidney cancer currently receiving systemic therapy. This was a randomized trial—50 patients. What's wild about this is that they had a single donor for all the stool that was used in the study.

So they had had a complete responder to immunotherapy. And that very kind and benevolent patient actually donated their stool and a sufficient quantity to supply both capsules, as well as FMT procedures done for the study. The trial met its primary endpoint. I don't think we had a huge deep dive of the data as yet, but I spoke to the investigators, who are working rapidly on publication, and they did meet their primary endpoint of improving one-year progression-free survival. So I view this effort from my Italian colleagues, Dr. Ciccarese and Dr. Iacovelli, as being another step to suggest that I think we're on the right path by trying to manipulate the microbiome in association with immunotherapy for kidney cancer.

This is by no means the only approach. If I were to say that we're the only kid on the block, that wouldn't be true at all. I mentioned Akkermansia at the outset in one of my slides—it’s a bacteria that's associated with favorable clinical outcome that was identified by a French group. And there's actually a drug now that is fortified with Akkermansia to try to get folks to the right level, so to speak, to augment outcome. And there's also this approach that I think is cool from companies like Microbiotica that are looking at consortia of bacteria. So you can actually look at not just one single strain, as we are, but maybe seven or eight, up to nine strains in this case of bacteria that may augment clinical outcomes.

So there's a whole host of really interesting approaches. Our group is really interested in better understanding how simple interventions like diet might improve outcomes. So one of my junior faculty, Charles Nguyen, who's pictured in the top right there, actually just won this Pilot Grant and now, more recently, a larger grant to support this work, looking at the role of fiber in modifying the gut microbiome in kidney cancer patients.

And my colleague, Dr. Wesley Yip—he's a terrific fellow who trained at Memorial. He did his yearlong fellowship there and now joined us as faculty at City of Hope as a surgeon. He's doing this study looking at adjuvant pembrolizumab and all the contexts we would use it clinically, and just adding some live bacterial products to that.

I wanted to close with this. This is a slide that I think is actually going to hopefully change the way that we think about the microbiome. Dr. Salvador Jaime-Casas, a terrific fellow that works with me now—he's from Mexico City, and he's applying for US residency programs next year in urology—he's actually doing a study where he's taking random samples of kidney tumor and then adjacent normal tissue. And we're going to subject that to intratumoral microbiome processing. I put on the slide here "confidential," but I don't mind sharing this with the audience. So Ashish, maybe I'll wrap up there and I’m happy to answer any questions that you have around these slides.

Ashish Kamat: Monty, thanks so much. I mean, obviously, you have a lot more you could talk about, but you did a nice high level and a little bit of a deep dive as well. The questions that often come up from folks—and it could be folks that are experienced and not experienced—is like now that patients are hearing this, like you said, they walk into the clinic saying, “Hey, I've got this probiotic or this microbiome,” like you said, “from Amazon, and I'm taking it.” So practically speaking, how would you counsel those patients? Can they continue? Should they stop? Are you like, “OK, do it. Just let me know so I can control for this?” What's your approach—practical approach?

Sumanta Kumar Pal: Yeah, I always really try to be a purist and stick to the evidence in this space. And I don't think we'd ever accept a systemic therapy based on a trial of just 30 patients until it had been validated in a larger series. So I just share that perspective with patients. I also introduce the potential for harm. There's this really nice paper in Science from Jennifer Wargo at your shop, which did this deep dive of fiber use and probiotic use in the context of melanoma.

Her work has really inspired our interest in looking at fiber. It really does suggest that fiber may enhance clinical outcomes with immunotherapy, and I view that as being a fairly benign intervention—I mean, fiber is a part of our diets anyhow. But it suggested—and this is quite curious—that live bacterial products may actually play a role in, if you use them willy-nilly (just the random stuff you're buying over the counter at GNC), impeding outcomes with immunotherapy.

So that paper in Science introduced the possibility that probiotics could do harm. And I think when patients hear that, they tend to be a little bit more convinced not to take that approach unless it's in the context of a clinical trial. So many issues around probiotics that we just don't have an answer to. I mentioned that we're doing trials to optimize dose. We need to understand the time frame in which people need to be taking these agents. So a lot of complexities that are still yet to be unraveled.

Ashish Kamat: That's a great point. And I have now patients coming in taking probiotics or microbiome to increase GLP-1 production because they can't get semaglutide. And we're like, “OK, we don't know what that does,” but it's just a confounding factor. The second question I wanted to ask you is, with all the work that you've done, obviously, you're doing work with single agent, folks are doing fecal transplants. Do you think there's a balance? Do you think, like with most immunotherapies, too much can actually be bad—not the wrong thing, but too much of the right thing? I know you're also doing dose escalation studies or mentoring folks that are doing those. Is there a sweet spot, Monty? What do you think?

Sumanta Kumar Pal: You hit the nail on the head with that one because there was this paper that just came out in Cell. And it's a really interesting read. It was the group from Gustave Roussy led by Dr. Laurence Albiges, and she's done a lot of pioneering work in this field. For years, she's championed Akkermansia as a potential bacteria that seems to be related to immunotherapy response. But this paper in Cell does a great job of characterizing patients who have what she terms dysbiosis. So these are essentially bad guts—guts with bad microbiota.

And in that paper, she suggests that there is a consortium of bacteria that can define an unhealthy gut. But with Akkermansia in particular, there's a sweet spot. So there's a point at which you might have low Akkermansia, in which supplementation might benefit. There's a situation in which you might have a sufficient amount of Akkermansia, and then there's a place in which you might have an excessive amount where it, again, impedes your clinical outcomes. So getting to that sweet spot, I think, is going to be really, really challenging. It really does reinforce, I think, the suggestion to do some of these dose escalation trials and really get a sense biologically of what would benefit the patient.

Ashish Kamat: Yeah, and then this whole discussion brings me back to memories I had when I was chatting with Curtis Nichols, whom I'm sure you're familiar with—the guy who did a lot of pioneering research with microbiome, but this was 25 or 30 years ago when the technology didn't really exist to be able to identify, other than doing actual cultures, and microbiome in the bladder correlating with so many neurological issues.

I think having someone like yourself leading the way and mentoring so many folks to do this kind of work, and, of course, Jen over here at Anderson—I think we're at the tip of the new iceberg, so to speak, and there's so much to discover and unpack that I'm sure we'll have you back on. But till then, thanks again for taking the time. Looking forward to seeing when the trial actually gets open. And any idea when it's going to open, Monty?

Sumanta Kumar Pal: We're hoping that it's going to open within the next 6 to 12 months. I think the NCI is going to mandate that. So we have no choice. We've got to get going quickly.

Ashish Kamat: Absolutely, great. Well, in short, thank you so much for taking the time.

Sumanta Kumar Pal: My pleasure.