Impact of CBM588 on gut microbiome composition and dysbiosis in patients receiving frontline immune checkpoint inhibitor (ICI) combinations for metastatic renal cell carcinoma (mRCC).
Authors: Dizman Nazli , Ebrahimi Hedyeh , Barragán Carrillo Regina , Meza Luis A , Bergerot Paulo Gustavo , Dorff Tanya B. , Hsu Joann , Zengin Zeynep Busra , Castro Daniela V. , Chehrazi-Raffle Alex , Tripathi Abhishek , Trent Jeffrey M. , Takahashi Motomichi , Oka Kentaro , Higashi Seiya , Caporaso Gregory , Lee Keehoon , Pal Sumanta Kumar 
Published: June 2024

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Background: Two recent randomized phase I clinical trials have provided compelling evidence that CBM588, a Clostridium butyricum-based live biotherapeutic, holds potential to enhance clinical outcomes in patients with mRCC receiving frontline ICI combinations (Dizman et alNature Medicine 2022; Ebrahimi et alASCO 2023). We examined the impact of CBM588 on gut microbiome composition in a combined cohort of these two studies to further investigate its impact on gut microbiome. Methods: We analyzed stool samples from two phase I randomized clinical trials that enrolled patients with mRCC treated with (1) nivolumab/ipilimumab (nivo/ipi) +/- CBM588 and (2) cabozantinib/nivolumab (cabo/nivo) +/- CBM588. We compared gut microbiome diversity and composition at baseline and week 12 between patients in the standard of care (SOC) arms (nivo/ipi or cabo/nivo) and those who received CBM588 in combination with a SOC regimen (SOC/CBM). Taxonomic profiling was performed using MetaPhlan v4, and changes in the abundances of clinically relevant microbial species from baseline to week 12 were assessed using the Wilcoxon matched pairs test. The ratio of Firmicutes/Bacteroidetes, a measure of gut dysbiosis, was computed across time points in the two cohorts. Results: Among 58 patients included in the analysis, 38 received SOC/CBM588 as first-line treatment. The median age of the overall cohort was 60 years (range: 36-90). The majority were male (71%), had clear cell mRCC (88%), and intermediate/poor risk disease (79%). In both the SOC and SOC/CBM cohorts, there were no statistically significant differences in alpha and beta diversity between baseline and week 12. Among clinically relevant species compared between baseline and week 12, Alistipes senegalensis decreased in both the SOC and SOC/CBM cohorts (log fold change [LFC] -0.82 [P=0.004] and LFC -0.36 [P=0.007], respectively), while Eubacterium siraeum decreased only in the SOC cohort (LFC -1.75 [P=0.005]). The Firmicutes/Bacteroidetes ratio increased from 89.0% to 96.4% in the SOC cohort, whereas a notable decrease was observed in this ratio from 100.0% to 75.7%. in the SOC/CBM cohort. Conclusions: Supplementation with CBM588 leads to a marked correction of gut dysbiosis and prevents the depletion of species previously associated with ICI response (i.e., Eubacterium siraeum). These findings provide a plausible mechanism for the enhanced clinical outcome with CBM588 now seen across two small, randomized trials. A phase III study is planned within the cooperative groups to evaluate the clinical activity and gut microbiome modulation capacity of CBM588 in combination with ICIs in mRCC.