The Gut Microbiome and Immunotherapy: New Research Explores CBM588's Mechanism in mRCC

Metastatic renal cell carcinoma (RCC) treatment commonly involves checkpoint inhibitors or a combination of a checkpoint inhibitor and a VEGF-targeted therapy like cabozantinib (Cabometyx) and nivolumab (Opdivo).

Previous studies suggest the gut microbiome composition affects immunotherapy outcomes. CBM588, a live bacterial product used in Japan, has become the target of research by investigators at City of Hope Comprehensive Cancer Center in Duarte, California. A previous study showed CBM588 improved response rates in patients receiving ipilimumab (Yervoy) and nivolumab.

In this current preliminary study, 30 patients with metastatic RCC received either cabozantinib plus nivolumab or cabozantinib plus nivolumab with CBM588. The CBM588 group had a higher response rate.

Initially, researchers hypothesized CBM588 increased Bifidobacterium species and microbiome diversity, but no significant changes were observed. An analysis of metabolic pathways revealed key differences in the downregulation of menaquinone (vitamin K) production pathways, whereas the CBM588 group displayed upregulation of some vitamin K production pathways.

Researchers, including Hedyeh Ebrahimi, MD, MPH, a medical oncologist at City of Hope, hypothesized that CBM588 improves response by enhancing vitamin K production, which may play a role in apoptosis based on previous studies.

This research is in its infancy, but further research is warranted to confirm this hypothesis and explore the specific mechanisms involved.

Ebrahimi presented these findings at the 2024 Genitourinary Cancers Symposium and discusses the basis for the study here.

Transcription:

0:05 | A little bit of background about CBM588: It is a light bacterial product. It's commonly used in Japan. In the previous study that we did at City of Hope, we saw that when we add CBM588 to all checkpoint inhibitor therapy in metastatic renal cell carcinoma, we will see better clinical outcome in patients. Their response rate was much higher in the arm that received CBM588.

But the other regimen that is commonly used in the setting of metastatic RCC was nivolumab with cabozantinib, which is TKI/VEGF targeted therapy. In the current study, we designed a kind of similar trial: phase one with 30 patients to get either a cabozantinib plus nivolumab in a standard dosage or cabozantinib plus nivolumab with the addition of CBM588.

0:47 | In the current study, we again see that those patients that receive CB588 in addition to this other treatment, have better clinical outcome. The response rate was much higher in the patient who received CBM588. We had a first hypothesis that maybe this increased clinical benefit was true, changing the composition of the microbiome in the patient's gut and increasing the Bifidobacterium species. But as we tested in the previous and current study, we didn't see any significant difference in terms of abundance of Bifidobacterium species.

1:24 | We had also thought maybe the composition changed, so we check the diversity of the microbiome composition in our patients, and there was not a significant difference between the Alpha diversity between posttreatment arms.

We looked further to see if there is a difference between the metabolic pathway that are happening in patients’ guts. To our surprise, we saw that in patients who receive cabozantinib plus nivolumab in standard dose without CBM588, 6 metabolic pathways that are functional in producing menaquinone, which is a form of vitamin K, had declined. At the same time in patients who receive CBM588, 2 pathways that has a function in producing vitamin K had increased.

Our thought in this study was that the hypothesis that we have is that there is a chance that CBM588 increases the response in our patients to increasing the production of metabolites that are used in part in creating vitamin K.