Exclusive Interview: Nazli Dizman, MD on RCC Immunotherapy with Gut Microbiome Modulation

In April 2022, we highlighted a novel phase 1 clinical trial published in Nature Medicine by Dizman and colleagues.1 In that trial, the authors reported on the results of augmenting combination nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) immunotherapy with a novel live bacterial product, CBM588 (Miyarisan Pharmaceutical Company), a strain of Clostridium butyricum.

In this exclusive interview, we discuss the trial with Nazli Dizman, MD, a resident physician at the Yale School of Medicine.

Akhil Saji, MD (AS): Welcome, Dr. Dizman. We are going to discuss your study on gut microbiome modulation in metastatic renal cell carcinoma (RCC). Before we begin speaking about the clinical trial, please describe the current treatment options for patients with metastatic clear cell RCC (ccRCC)?

Nazli Dizman, MD (ND): The treatment landscape for ccRCC has changed remarkably in recent years. We now have several therapeutic options that we can offer our patients. Immunotherapy-based combinations comprise the currently available first-line options.

The nivolumab and ipilimumab combination was the first to show improved outcomes in this space. It was followed by immunotherapy and targeted therapy combinations, including pembrolizumab plus axitinib, pembrolizumab plus lenvatinib, and cabozantinib plus nivolumab. With these therapies, we have seen objective responses in more than 50% of patients, meaning overall survival rates are now surpassing 4 years for patients with metastatic ccRCC.

Unfortunately, however, most patients will have progression of disease at some point. After progression following first-line treatment, guidelines recommend switching to targeted agents, mainly multikinase inhibitors, mTOR [mammalian target of rapamycin] inhibitors, and other combinations. There are a number of novel therapeutics that have shown promise in earlier-phase 0 studies and are being tested in clinical trial settings. Clinical trial enrollment should be considered an option for patients at any stage of this disease.

AS: Thank you for that context. Your phase 1 study is notable because it uses the novel compound CBM588, which augments the gut microbiome. Could you please start by providing an explanation of gut microbiome modulation?

ND: Beginning with the human microbiome project, as well as several other invaluable efforts from around the globe, we have achieved a more comprehensive understanding of the link between the gut microbiome and several different diseases. The evidence shows that certain microbial species, the function of these species, microbial diversity, and the function of microbial communities as a whole play a role in several pathologies, including cancer.

Our group is among those who are aiming to modulate the gut microbiome using different approaches. Different dietary strategies, probiotics, prebiotics, and fecal microbiome transplantations are the most commonly studied means of modulating the gut microbiome in an effort to improve outcomes and response rates, prevent adverse events, or perhaps overcome resistance to available therapeutics. That is the overall concept behind gut microbiome modulation.

AS: Let’s talk next about CBM588. What is it, and how does it function?

ND : CBM588 is a live bacterial product. It’s an anaerobic spore-forming bacterium that produces high amounts of butyric acid in the gut lumen. As we know, butyric acid is a short-chain fatty acid that is beneficial for several organ systems, and it also provides good food for some other commensals in gastrointestinal (GI) microbiota. CBM588, specifically, is a butyrate-producing bacterium that resides in the GI system and has been shown to be associated with improved outcomes with immunotherapy.

From a clinical standpoint, CBM588 is a common product used by individuals in Japan. One study in Japan retrospectively looked at clinical outcomes in patients with non-small cell lung cancer (NSCLC) who did or did not receive CMB588 in addition to immunotherapy. The results showed improvements in progression-free survival and overall survival outcomes in the patients who received CBM588. In our study, CBM588 was administered as an 80-mg powder that patients mixed with water and drank it 2 times a day.

AS So it seems like a safe intervention that is easy for patients to use.

ND Yes. We had no complaints or issues with noncompliance in our study cohort.

AS: Tell us about the design of your study and some of the overall results.

ND: The study was conducted at City of Hope in Los Angeles, California, and enrolled 30 patients. At the end of the study, 29 patients were available for evaluation of treatment response and outcomes. We randomized patients with ccRCC right after diagnosis of metastatic disease. They were randomized to receive either nivolumab and ipilimumab, which is the standard of care (SOC) treatment, or nivolumab and ipilimumab along with CBM588.

We followed our patients for at least 12 weeks and collected stool samples at baseline and week 12. We also collected blood samples at baseline and week 12. The primary endpoint of the study was to determine the change in abundance of Bifidobacterium species from baseline to week 12 in the 2 treatment arms. Our goal was to see if the addition of CBM588 to SOC treatment would increase the abundance of Bifidobacterium in patients.

AS: What about secondary endpoints?

ND: The secondary endpoints included clinical outcomes, such as adverse event rates and circulating cytokine levels. We also reported the results of gut microbial profiling at baseline versus week 12 and assessed gut microbiome function in metabolic pathways.

AS: What were your findings?

ND: In terms of the primary endpoint, we did not observe a statistically significant increase in the Bifidobacterium abundance in patients who received nivolumab/ipilimumab and CBM588. There also was no observed increase or decrease of Bifidobacterium spp. in patients in the nivolumab+ipilimumab-only arm. However, in the specific subpopulation of patients who responded to nivolumab+ipilimumab and CBM588, there was a significant increase in Bifidobacterium species.

When we looked at the clinical outcomes, we found rather interesting results in the  nivolumab+ipilimumab and CBM588 treatment arm. Progression-free survival was 12.7 months with nivolumab+ipilimumab and CBM588 arm, compared with just 2.5 months in nivolumab ipilimumab arm. Patients in the experimental arm also had a response rate of 58% compared with 20% in the SOC arm.

We also examined several translational endpoints. When we compared the baseline and week 12 blood samples of patients given nivolumab+ipilimumab and CBM588, we observed an increase in chemokine levels. We also used stool samples to evaluate the abundance of the metabolic pathways and found that metabolic pathways associated with short-chain fatty acid consumption increased in abundance from baseline to week 12 with CBM5888 supplementation.

In terms of adverse events, we found that our patients tolerated CBM588 very well. We had almost 100% compliance and there were no CBM588-associated adverse events reported by patients. In terms of immune-related AEs, I believe they were comparable to what we have seen in previous studies of nivolumab+ipilimumab.

AS: Those are very promising findings. When you first published the study, and on Twitter especially, a lot of people were really interested and excited about the results. What are the future directions in gut microbiome research?

ND: In terms of the future direction of microbiome research, it’s important to mention that several investigators around the world are looking at ways to modulate the gut microbiome to improve outcomes. For example, we currently have an open study at City of Hope looking at use of CMB588 in combination with cabozatinib. I think, for the future, our goal should be to conduct very robust studies with a powerful translational component, so we can understand exactly which patients need microbiome modulation to improve outcomes.

 

Reference

  1. Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. [Online ahead of print.] Nat Med. 2022;10.1038/s41591-022-01694-6. doi:10.1038/s41591-02201694-6