Combining the live bacterial product CBM588 with checkpoint inhibitors improved progression-free survival.

  • Major Finding: Combining the live bacterial product CBM588 with CPIs improved progression-free survival.

  • Concept: Tumors were reduced, but no change to Bifidobacterium spp. within the gut microbome was observed.

  • Impact: This combination is relatively safe and revealed an improvement to clinical outcome in patients with mRCC.

The gut microbiome has been shown to modulate response to cancer immunotherapy treatments in many cancer types, including metastatic renal cell carcinoma (mRCC). Despite the combination of nivolumab (PD-1 inhibitor) and ipilimumab (CTLA4 inhibitor) being the standard of care for mRCC, many patients do not achieve a response. Preclinical studies using the live bacterial product CBM588, which contains Clostridium butyricum, showed its ability to enhance growth of Bifidobacterium spp., which has been shown to reduce tumor growth and checkpoint inhibitor (CPI) response. Based on the results of these preclinical studies, Dizman, Meza, Bergerot, and colleagues conducted a prospective randomized phase I trial to evaluate the effects of CBM588 in 30 patients with mRCC being treated with nivolumab and ipilimumab. The primary endpoint for this study was characterization of the effect of CBM588 on microbial populations within the gut, especially Bifidobacterium spp., at baseline and at 12 weeks, which was not met, as significant differences in Bifidobacterium spp. were not observed. However, Bifidobacterium spp. were found to be increased in responders, and median progression-free survival was also significantly improved in the nivolumab–ipilimumab plus CBM588 group. Objective responses were observed in 11 (58%) patients treated with nivolumab–ipilimumab plus CBM588, while only two (20%) demonstrated this response in the nivolumab–ipilimumab only group. Furthermore, tumors were reduced in 14 (74%) patients within the nivolumab–ipilimumab plus CBM588 cohort as compared to five (50%) in the nivolumab–ipilimumab only treated patients. Investigation into safety revealed no statistical difference between the treatment groups. Additional exploratory analysis demonstrated an increase in the dTDP-β-L-rhamnose biosynthesis pathway, induction of chemokines including CCL2, CCL4, CXCL9, and CXCL10, and no change to regulatory T-cell populations in the CPI plus CBM588 group, supporting CBM588's immunomodulatory properties. This study, therefore, indicates an improvement to CPI response upon addition of CBM588 in mRCC, suggesting the need for further investigation into this treatment combination in a larger sample size as well as between different tumor types.

Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med 2022 Feb 28 [Epub ahead of print].

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