Exploring the Link between Gut Microbiome and Immunotherapy Response in Metastatic Renal Cell Carcinoma - Nazli Dizman

July 7, 2023

Pedro Barata speaks with Nazli Dizman regarding her work on a Phase I trial involving immunotherapies and gut microbiome in metastatic renal cell carcinoma. Dr. Dizman discusses the rationale behind the study, highlighting the increasing recognition of gut microbiome's impact on disease processes, including cancer. The trial tested CBM588, a bacterium used in Japan for over 50 years, which was expected to influence gut microbiome and immune responses. Results revealed an improvement in clinical outcomes and a change in bifidobacterium species in patients who responded to CBM588. They also discuss ongoing and upcoming trials applying similar concepts to different combinations of immunotherapies. Finally, Dr. Dizman touches on other research exploring the impact of dietary interventions and microbial products on the gut microbiome and immune response.


Nazli Dizman, MD, Internal Medicine Resident, Yale Department of Internal Medicine, Yale School of Medicine, New Haven, CT

Pedro C. Barata, MD, MSc, Leader of the Clinical GU Medical Oncology Research Program, University Hospitals Seidman Cancer Center, Associate Professor of Medicine, Case Western University, Cleveland, OH

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Pedro Barata: Hi there. My name is Peter Barata. I'm a GU medical oncologist at Case Western University, Seidman Cancer Center in Cleveland, Ohio. And I'm really happy to be joined today by Dr. Nazli Dizman. She's a resident at Yale School of Medicine, actually currently applying for fellowship, and already with a fantastic track record including a Nature Medicine paper that we're going to be chatting today. But first, welcome Nazli, thanks for taking the time to chat with us.

Nazli Dizman: Thank you so much. It's my pleasure. Thanks for having me.

Pedro Barata: Absolutely. So listen, congratulations, great job publishing the data, and then presenting long-term results at IKCS in San Diego, on your Phase I trial, ipi/nivo with or without CBM588 in metastatic renal cell carcinoma. Right. And this is such a hot topic right now. I feel like there's a lot of us who don't know a lot about it, and we do want to know more about it. So we all going to people like you and Monty Pal and others to learn. Right?

So I guess, for those of, for us actually, who are less familiar with gut microbiome, right. Can you just walk us through the process when you and Monty were kind of brainstorming ideas for this trial? Why ipi/nivo with CBM588, why did you pick CBM588? Can you share with us a little bit of the thought process behind that?

Nazli Dizman: Yeah. First of all, thank you for the kind words. In terms of the process, I think in the past few decades, there had been an accumulating data about the impact of gut microbiome on different disease processes, which includes cancer. In earlier, in 2017/18, we have seen the first studies looking at large samples, large sample sizes, and I'm trying to understand whether there's an association between outcomes and the different characteristics of gut microbiome.

They looked at different types of bacteria, they looked at the composition of the gut microbiome as a whole, as a community, and they also looked at the gut microbiome diversity, and other rare parts of gut microbiome, like viruses, like fungi. So we came to understand that there was a link between immune system and gut microbiome composition. Mainly, the gut microbiome diversity, and a few different types of bacteria, were related with risk past immunotherapies. In early, again in 2018, we had one paper already published, and in the area of targeted therapy, is looking at the gut microbiome profile of patients with renal cell carcinoma, and we comparing a bit to healthy individuals and trying to find the differences.

So we were familiar with the gut microbiome research, and at that time, given that data, we became interested in doing gut microbiome modulation. We have first published a paper actually, looking at yogurt supplementation in patients receiving targeted therapies, and its impact on gut microbiome and outcomes. We didn't have extremely promising findings with that study. But then, we met this pharmaceutical company that is producing CBM588. It anerobic bacterium that has been used in Japan for more than 50 years, in mainly GI conditions. And it was shown that it increases the levels of short chain fatty acids in gut. And we already knew that short chain fatty acids are associated with different bodily functions, and including immune system. So we wanted to test CBM588, in patients receiving immunotherapies, and understand its impact on the gut microbiome, outcomes, immune response, and the gut microbiome function itself. So the study came alive with this history, and the results were published earlier in April 2022, and we had the long-term follow up data in IKCS.

Pedro Barata: So actually great, I mean, fantastic presentation, Nazli. So that's exactly what I would like to ask you next as a follow up. We know it landed in a very prestigious journal, congratulations for that. And you are now presenting the long-term results of that. So can you summarize for the audience, overall, what did you see? Or rather, what did you see being confirmed with more follow up?

Nazli Dizman: Yeah. So I'll summarize the first paper really quick first. In the study, we compared the gut microbiome composition with the baseline and we to all samples, and nivolumab/ipilimumab group, and nivolumab/ipilimumab and CBM588 group, and trying to understand whether there was a change in the bifidobacteriumbacterium species in stool samples. That is because bifidobacteriumbacterium consumes short chain fatty acids, and we expected that the bifidobacterium would increase and improve the outcomes, because multiple studies in the past showed that bifidobacterium is associated with better outcomes with immunotherapy.

So we found a change in bifidobacterium species in patients who responded to CBM588. And we also observed a significant clinical outcome improvement in patients who receive CBM588. Now, that's why we wanted to present the long-term follow up data. Now with a median of 27 months of follow up, we have a progression-free survival of 36 months in patients who receive CBM588. And in patients who responded to treatment, responses were durable, with a median duration of response of 30 months. Again, response rate was higher in the patient group who received CBM588, compared to the patient group received standard no care in nivolumab and ipilimumab.

Pedro Barata: So very interesting results indeed. And seems to be the benefit of changing the gut microbiome seems to be persistent over time. Are there any ins that you know see kind of the plateau, or the curve, suggesting that more durable responders? When you look at those curves, what are your thought process? And the next question I have for you as well is, we are talking about IO/IO with a great rationale. Do you think the same thought process can be applied for other IO based combos including IO/TKIs, for example?

Nazli Dizman: Yeah. Yeah, great question. I think I have to first disclose, that this was a Phase I study and the sample size was small, and the clinical outcomes were not the primary endpoint of this study. Though, when I look at the results solely in the nivo/ipi CBM arm, I see the plateau at the end. And at the same time, as I told, the duration of response was almost 30 months by the data cut off, again, two months ago. So I would say that the responses are durable, with the sample size of 19 patients in that arm.

If you wanted to compare both arms, I think things get more complicated, because unfortunately, nivo/ipi arm performed worse than what we would expect, based on the historical data sets of nivolumab and ipilimumab. Having said that, I could highlight that the nivo/ipi CBM arm performed better than what we would expect from the historical data sets of nivolumab and ipilimumab.

Pedro Barata: You're absolutely right. I think the control arm, you correct me if I'm wrong, right? Response is around 20% or so.

Nazli Dizman: Yeah.

Pedro Barata: And the progression free survival is very short, isn't that right?

Nazli Dizman: One and a half months, yes.

Pedro Barata: Yeah. No, no, but go ahead. I guess the question is, to your point, right, this is a Phase I. We perhaps need to see if we can prove the point in a larger population. But I have to say on the design, you guys designed it at two to one. So you kind of predicted a benefit, which is really well thought, in my opinion. So I'll let you comment on whether or not you think this is being explored, or will be explored, with ipi/nivo in even larger studies, but also IO/TKIs, for example.

Nazli Dizman: Yeah. There's actually an ongoing study with cabo/nivo in first-line setting, with CBM versus just the standard of care cabo/nivo in intermediate and high-risk patients with RCC. We are about to complete that, but we haven't analyzed the data set yet. So that is pretty exciting, to be able to answer your questions. But it wouldn't be surprising to see an improvement in outcomes, or a change in the gut microbiome composition as well, because I think there is data suggesting that the combination RGEF and IO, the success of this combination comes from the immunomodulatory effects of RGEF inhibitors as well. So if there's an immunotherapy and our agent is acting on immune activation, then it wouldn't be surprising to see an improvement in outcomes in that study as well.

In terms of larger data sets, I think that is really important to understand these questions. Whether CBM588 is actually improving clinical outcomes? And for that, we are planning to start a Phase III randomized study, mainly in Europe, comparing nivolumab/ipilimumab/placebo and nivolumab/ipilimumab/CBM588, in first-line treatment of intermediate and high-risk patients with clear cell and/or sarcomatoid renal cell carcinoma.

So this study's going to help from clinical standpoint, and also, it's going to populate a large amount of samples from patients, from almost 700 patients. So we are hoping that it would help us understand the real impact of CBM588 on both gut microbiome and outcomes.

Pedro Barata: Right. That's really exciting. Thank you for highlighting a couple of studies that are either planned or ongoing, because it will help answer those questions. Thank you for highlighting that. Great job.

I guess, final question for you, are you aware of any other compounds exploring gut microbiota you'd like to highlight beyond CBM588?

Nazli Dizman: Meaning that different microbial products that are being studied. Not specifically in renal cell carcinoma, in terms of single strain or multi-strain bacterial product, but there are different studies in Phase I level, Phase I stage, looking at different compounds. Most of them are multi-strain bacterial products, that are combination of different bacterial strains that are known to be associated with immune response. And there are a few studies ongoing with dietary interventions. I think they enroll patients with renal cell carcinoma in a study in MD Anderson, looking at the impact of high fiber diet on gut microbiome and outcomes with immunotherapies.

Pedro Barata: Well fantastic. Super interesting conversation, Nazli. Thank you so much for taking the time. Again, congratulations. Great job. Your future is bright, and we're just happy that you took the time to sit down with us, and share your thoughts and knowledge for us today. So thank you. Good luck. And I have a feeling we're going to be talking soon again.

Nazli Dizman: Yeah, that would be wonderful. Thanks for having me here. And thanks for the opportunity to share our past results and future plans.

Pedro Barata: Absolutely. Thanks.

Nazli Dizman: Thank you.