The Uromigos Episode 103: Targeting the Microbiome Increases the Activity of Immune Therapy in Renal Cancer

Interesting preliminary data suggest that microbiome modification can impact immune-oncology clinical efficacy in metastatic renal cell carcinoma. More work needs to be done, but The Uromigos and Monty Pal discuss how these data are intriguing. View the ASCO abstract.

Episode Transcript

Brian:
All right, welcome everyone to another ASCO podcast. We’re joined by our good friend and colleague, Monty Pal from City of Hope. And this is actually a two-fer podcast. We’re going to talk about his IPI-NIVO plus minus a microbiome affecting agents in kidney cancer. And then we’re going to pivot to his oral presentation in bladder cancer.

So, Monty, welcome again. We know you’ve been on before. Thank you for taking the time. Let’s talk about the kidney cancer one first. You’ve done a lot of microbiome work in kidney cancer. So, introduce yourself briefly and then give us a little background to that study and maybe some of the high-level results.

Monty Pal:
Yeah. Hey guys, I’m Monty GU Medical Oncologist at City of Hope. Great to be back on the program. So, I’ve been really interested in the microbiome. And I think we’ve seen over the past couple of years, a lot of work tying the composition of the microbiome to the impact of immunotherapy.

We’ve had some work previously suggesting that you could predict toxicity with TKIs with the microbiome, but I’ve really been looking for a way to modulate it and really see whether or not we could drive some impact from it.

So, this actually takes a drug CBM588, which is the strain of Clostridium butyricum. And I can tell you a little bit more about that, but basically our premise is that this may modulate the microbiome in a favorable way and enhance the effect of immunotherapy.

Brian:
And so, take us through the study design. It was basically IPI-NIVO plus-minus, is that correct?

Monty Pal:
Yeah. There’s actually a really good story behind this one, Brian, if you’ll indulge me for a second. I had a fellow named Paulo Bergerot who’s now in practice down in Brazil. He’s one of the co first authors on this abstract here.

And so, he shows up at the Vail conference and we had a concept that we proposed there, and I know you’ve mentored at the Vail conference a bunch of times, and the concept that we proposed initially fell through. So, we were scrambling at the last minute to come up with a concept for him.

And we thought, okay, well NIVO-IPI is at that point in time, the emerging standard for renal cell. We had access to this compound, which was produced by a Japanese company that really has this impact on the microbiome. And we thought we’d throw the two together in a small, randomized study.

So, as you know, the Vail workshop is really this bastion for developing really unique clinical trial design. So, we devised this 30-patient study with a two to one randomization where two patients get NIVO-IPI plus CBM588 and one patient gets NIVO-IPI alone.

Tom:
Before you get there, Monty, do you want to just explain on this microbiome about why dynamic changes to the microbiome may facilitate the activity of immune checkpoint inhibitors? Why the biology of that might work?

There were a series of science papers, and I think it was on the front page of one of these big journals, not that long ago. Do we know why the microbiome might be a good place to target?

Monty Pal:
Yeah. I think that the true answer to that is we don’t know Tom, to be honest with you, but when you think about the microbiome, the microbiome is constituted by a trillion bacteria that lined the gut. Most of it is sort of sitting in the colon, about 96%.

And it really does elicit a tremendous impact on systemic immunity. So, you have release of TGF beta, you have release of specific cytokines from the gut and those can really drive the immune response systemically. I think that’s the general premise.

So, this particular agent that we’re using, Clostridium butyricum, sits in the gut. It releases butyrate, it’s a spore that travels down to the colon and releases butyrate. And we think that it’s bifidogenic. So, if you look at some of those science papers that you just cited, you’ll notice that bifidobacteria species are ones that tend to be associated with response.

It’s actually a tall order to just feed patients bifidobacterium, because it just gets digested in the gastric acid and other elements of the GI tract. So, this is a clever way to really produce a bifidogenic environment within the gut. That’s what you were really going for biologically.

Tom:
So, sorry to interrupt you. You got two to one randomization. Talk me through your endpoint because they’re not traditional.

Monty Pal:
They’re not, they’re not, no. And as you can imagine with 30 patients in the study, Tom, we really couldn’t power this to look at progression free survival or overall survival. That would just be too tall an order. So, again at the Vail conference, Paulo receives some suggestion to maybe power this towards a biologic endpoint.

So, we actually thought, okay, from a biological perspective we’re giving Clostridium butyricum, we hope the impact is going to create a bifidogenic environment. So, let’s make the primary endpoint, the change in bifido species from time A to time B. So that’s ultimately what we power the study towards. And you can do that with small numbers. You can look for some of these exploratory biological endpoints.

Tom:
And you measure that in the stool, Monty?

Monty Pal:
Exactly. So, we collect stool baseline, several other time points, but the primary endpoint is centered on week 12. So, you have a nice correlation there around the time the patients are getting their first set of scans as well.

Tom:
So, Monty, you have a trial with two samples as your primary endpoint.

Monty Pal:
That’s right. That’s right.

Brian:
I’ve always said your work was- [crosstalk 00:05:29]

Tom:
That’s very impressive. Monty. So, did you hit your primary endpoint, Monty? What did you show your dynamic changes?

Monty Pal:
So, we did not. So, we did not. So, I’ll tell you that the primary endpoint of the study was looking at the change in bifido from based 12 weeks. We didn’t see that, but what you’ll see embedded in Luis’s slides, Luis is a really talented fellow from Peru who’s working with me now.

What you’ll see in his slides is that we did see an increase in bifido species amongst responders to therapy. So, it actually does support the biologic premise in patients who are responding to the combination of NIVO-IPI plus CBM, you see this big jump in bifidobacterial species.

But, Tom, I think that even though progression free survival response rate, et cetera, were all secondary endpoints, very, very important.

I’m sorry [crosstalk 00:06:24] My kids are going crazy in the background.

But what I was going to say is, who kind of cares about the primary endpoint here it’s interesting. Our secondary endpoints were pretty spectacular. If you look at the waterfall plots, if you look at the Kaplan Myer occurrence for progression-free survival, you’ll see that there was really a sort of standout benefit with the combination of NIVO-IPI with CBM588, with the huge caveat of there being small numbers.

I think there’s a pretty compelling signal here. So, we’re looking forward to moving forward with this.

Brian:
Monty, do you know what bifido generation would be in the absence of IPI-NIVO? Is there a reason to believe the immunotherapy is affecting it? I’m trying to get to cause and effect here. What’s the directionality?

Monty Pal:
Yeah, no, that’s a great point. So, if we were to just give NIVO-IPI alone, what would the effect on bifido? Is that what you’re asking, Brian?

Brian:
Yeah, or if you just give the drug alone in the absence of systemic therapy, what happens? I don’t know if those experiments have been done.

Monty Pal:
They have been. There’s a nice paper in Eye Science that looks at CBM588. So, you can see some of the biological effects that we’re looking for, played out in animal models in that study.

I would also say too that from, and again, jumping to the clinical results here. The clinical results that we’re seeing here are actually bolstered by a pretty sizable retrospective study in lung cancer.

So, there’s a study published in Clinical Immunology Research about two years ago. They looked at 120 patients with non-small cell lung cancer, getting checkpoint inhibitors.

Those patients that got CBM588, which again, this drug is commercially available in Japan, actually had a very pronounced benefit progression-free survival and overall survival. So, these results are actually fairly consistent with what’s already out there.

Brian:
One more question, are there ethnic differences in microbiome? or the way that the different ethnicities would process this particular product?

Monty Pal:
Yeah, that’s something I’ve thought a lot about, Brian, and again, I’m going to refer back to those science papers that Tom brought up. So, there was one from the University of Chicago group, from Tom Gajewski. There was one from Jennifer Wargo at MD Anderson, one from [inaudible 00:08:37] and Gustave Roussy.

What was really interesting is if you really dive deep into the data from all three of those papers, there were different bacteria in each of those studies that seemed to predict the response to immunotherapy. So, I 100% agree with you Brian, or agree with the suggestion that there may be differences amongst patients of varying ethnicity with varying dietary intake.

We tried to the best of our ability to control for that in our study. We took very copious dietary logs in this trial. Of course, the main focus there was to make sure that patients weren’t taking bacterial fortified foods alongside the probiotic that we were administering.

Tom:
Monty, your hazard ratios in progression-free survival are outrageous in some respects. It looks like the two curves grow apart right at the beginning, stay apart. The OS looks terrific. It’s underpowered at the moment, obviously it’s 30 patients.

There are two questions. The first is, I’m not aware of that many other randomized trials looking at the microbiome in combination with immune therapy. Is this developing in terms of a new field of what we should be doing? And so, then the next question from there is what do we do next with these data?

Monty Pal:
I’ve been following this field very closely and there’s been a lot of pharmaceutical interest. AstraZeneca had a partnership with a company called Seres, develops microbiome-based products.

I’m not exactly sure where that stands, but their main focus is on melanoma. There’s a company called Avelos that actually developed a microbiome product in combination with immunotherapy for triple negative breast cancer that was reported at San Antonio this past year. I thought the results there were pretty modest.

But I think we need to see more trials like this. We just can’t let those science papers gather dust. I think it’s important that we build on that and try to develop some really for thoughtful prospective studies.

And I agree with everyone’s critique that this was a very small study, but again, when you look at the magnitude of benefit that you’re seeing with the live bacterial product here, the probiotic, it’s hard to argue against looking at it further.

Brian:
Is it enough to convince BMS or somebody to say, “Hey, let’s do a big, randomized study or not?” Obviously, there’s different motivations here in that kind of study or is it maybe going to a bigger randomized phase two, or what do you think the realistic next step is?

Monty Pal:
Yeah, well this podcast is my first sales pitch for that, Brian, but I [crosstalk 00:11:19].

I think this is a compelling enough signal to explore this further. Now while those plans are ongoing, I will say that we receive funding to do a study that looks at CABO-NIVO plus or minus this live bacterial product.

And I think what we’re hoping to show there or determine there is if, whether or not, you have added influence of the TKI, whether or not you have the same sort of impact on clinical outcome. Or if it’s blunted.

Brian:
Would diarrhea, if you had TKI induced diarrhea, would that potentially blunt it? Because you’re getting rid of this or no, is that not the case?

Monty Pal:
That’s entirely possible. Some of that, we have a paper in CCR back in 2015 and you can actually see that folks that develop diarrhea with TKIs have a very different constitution of their gut microbiome. So that’s entirely possible, Brian, and I think that’s exactly the sort of thing we want to tease out.

We want to make sure we don’t just dive into this head on say, oh, if you’re getting AXI-PEMBRO or LEN-PEMBRO or CAB-NIVO, just tack this on. We really want to have some good initial translational evidence to suggest that we’re making the same biologic effect happen.

Brian:
And the CABO-NIVO study you just cited is a randomized phase two?

Monty Pal:
It’s got the exact same design line as this one. We basically did a cut and paste of the protocol. So, Paulo wrote that first protocol. Luis, who’s the first author of this study, wrote that one. And we’re about to activate in about a month or so.

Tom:
We’d love to take part.

Brian:
You should increase the numbers. I think you could get, standard of care. So, I think it’s such an easy intervention that you’re never going to have definitive numbers, but you could have 50 and 30 or 15 and 25.

Tom:
It’s not like we’ve got a billion new ideas in drug development and kidney cancer right now. This is a really good opportunity.

Monty Pal:
Yeah, absolutely. This is easy. It’s cheap. I think there’s so many merits to taking this approach.