Microbiome influence on renal cell carcinoma and promising clinical outcomes

The science surrounding the human microbiome has advanced rapidly in recent years, and research is also expanding into the field of oncology. City of Hope Comprehensive Cancer Center's Hediye Ebrahimi, MD, public health nurse, and other researchers set out to investigate the potential link between the gut microbiome and metastatic renal cell carcinoma (mRCC). I tried.

In a phase 1 trial (NCT05122546), patients with mRCC received a combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) with or without the addition of CBM588, a live bacterial product. This study aimed to understand the impact of her CBM588 on clinical outcomes.

Previous research conducted at City of Hope has shown that the composition of the gut microbiome can influence the effectiveness of immunotherapy, with the addition of CBM588 to checkpoint inhibitor therapy leading to higher response rates. It has been suggested that there is.

The current trial enrolled 30 patients who were randomly assigned to receive cabozantinib plus nivolumab or cabozantinib/nivolumab combination therapy plus CBM588. The addition of CBM588 improved clinical outcomes and increased response rates.

This hypothesis initially focused on changes in the abundance of specific bacterial species, but no significant changes were observed. However, differences were observed in the metabolic pathways associated with vitamin K production. Patients who received CBM588 showed an increase in the pathways that produce menaquinone, a form of vitamin K, while those pathways decreased in patients who did not receive CBM588.

This study was small and the results are preliminary but encouraging and require larger trials to confirm. The potential role of CBM588 and vitamin K in enhancing response to mRCC treatment remains a subject of exploration and may contribute to immunotherapy and a better understanding of the microbiome.

In an interview with Targeted Oncology^TMEbrahimi discussed the research and results presented at the upcoming conference. 2024 Genitourinary Cancer Symposium.

Kidneys, adrenal glands, genitourinary system: © Leo Viktorov – Stock.adobe.com

Targeted Oncology: Can you outline your studies on the evolution of microbial communities in metastatic RCC patients receiving this combination of cabozantinib and nivolumab with or without CBM588?

Ebrahimi: As you may know, there are almost always two first-line treatment options for metastatic renal cell carcinoma. One is to use two checkpoint inhibitors, and the other is a combination of one checkpoint inhibitor and one VEGF-targeted therapy, such as cabozantinib and nivolumab.

We have conducted several previous studies showing that a patient's gut microbiome composition can influence immunotherapy outcomes. Building on this, our previous study at City of Hope investigated whether both checkpoint inhibitors, ipilimumab and nivolumab, and CBM588 increased or decreased outcomes in patients receiving ipilimumab and nivolumab. , or tested to see if it has any effect.

A little background on CBM588: CBM588 is a live bacterial product. In Japan, a retrospective study showed that patients with non-small cell lung cancer who received immunotherapy and took CBM588 had better outcomes. This hypothesis arose from initial research in Japan.

In our previous study at City of Hope, we found that adding CBM588 to dual checkpoint inhibitor therapy in metastatic renal cell carcinoma improved clinical outcomes for patients. The response rate was much higher in the group receiving CBM588.

Another regimen commonly used in cases of metastatic RCC is a combination of VEGF-targeted therapy and immunotherapy. In the current study, we designed a phase 1 trial of either cabozantinib plus nivolumab at standard doses or cabozantinib plus nivolumab with the addition of CBM588 in 30 patients with advanced RCC.

What did you find out as a result of your research?

The current study also found that patients who received CB588 in addition to this standard treatment had better clinical outcomes. Patients receiving CBM588 had a higher response rate. We changed the composition of the patient's gut microbiome to increase Bifidobacterium species and made the initial hypothesis that this increased clinical benefit was true. However, similar to previous studies, no significant changes were observed in the abundance of Bifidobacterium species in either arm of the study.

We also checked the diversity of patients' microbiome composition and found no significant changes in alpha diversity between baseline and post-treatment in either group.

We further investigated whether there were differences in the metabolic pathways occurring in the gut. Surprisingly, they found that patients who received standard doses of cabozantinib and nivolumab without CBM588 had reduced metabolic pathways that function to produce menaquinone, a form of vitamin K. At the same time, the pathway that functions to produce vitamin K was increased in patients receiving CBM588.

Our idea in the current study was that CBM588 may enhance patient response by increasing vitamin K. There are several data from previous clinical and preclinical studies supporting that vitamin K plays a functional role in cancer apoptosis. cell.

For example, a study on hepatocellular carcinoma showed that patients who received vitamin K in addition to sorafenib, a treatment used in hepatocellular carcinoma, had better outcomes. Therefore, we reasoned that CBM588 increased the production levels of menaquinone or vitamin K, which increased patient response.

Could you explain the methodology of this study?

This study enrolled patients with metastatic or advanced renal cell carcinoma. Since this was first-line treatment, the patient should not have received any systemic treatment for metastatic disease. They must have a confirmed histological report of clear cell, papillary, or sarcomatoid pathology.

Thirty patients participated in this trial. 2:1 randomization was performed. That is, 20 of the 30 patients received cabozantinib plus nivolumab plus CBM588, and 10 patients in the control group received standard doses of cabozantinib plus nivolumab alone.

We evaluated their outcomes, both clinical and radiological outcomes. She had imaging tests every 3 months and was regularly evaluated by a clinician to assess if she was progressing. Patients were also asked to collect stool samples at baseline and week 13 to assess their gut microbiome composition.

Did changes in microbial function correlate with clinical outcomes?

The response rate was much higher in the group, CBM588. Regarding partial response, in the CBM588 group, 74% of patients had a partial response, whereas in the control group, only 20% of patients had a partial response, so the response rate was higher in the group. It was much more expensive.

When we checked the function of the gut microbiome, we found that the CBM588 group had an increase in pathways that function in menaquinone production, while the control group had a decrease in the proportion of those pathways. There are significant differences in the function of vitamin K production between the two arms. At the same time, there was an increased response in the CBM588 group, which is our hypothesis. The gain was due to increased production of menaquinones.

How will these findings contribute to understanding immunotherapy and the gut microbiota in metastatic RCC?

I know there's something substantial. [amount of] There is growing interest among the patient community about the role of CBM588, and the microbiome in general. But this study that we did here was a small study. Please note that although there was a positive response, no clinical intervention can be concluded at this time. Larger studies are needed before we can suggest or advise patients whether or not to undergo any type of microbiome therapy.

At this time, we do not know the exact role that justifies a change in practice. We look forward to SWOG soon starting a Phase 3 trial with her CBM588 in patients with metastatic renal cell carcinoma. Discussions are underway to begin a Phase 3 trial involving a much larger number of people. The results of this future trial may further clarify our clinical practice. We are also considering future studies to evaluate the potential role of vitamin K and increased patient response.