Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial

Abstract

Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer. CBM588 is a bifidogenic live bacterial product that we postulated could augment CPI response through modulation of the gut microbiome. In this open-label, single-center study (NCT03829111), 30 treatment-naive patients with metastatic renal cell carcinoma with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomized 2:1 to receive nivolumab and ipilimumab with or without daily oral CBM588, respectively. Stool metagenomic sequencing was performed at multiple timepoints. The primary endpoint to compare the relative abundance of Bifidobacterium spp. at baseline and at 12 weeks was not met, and no significant differences in Bifidobacterium spp. or Shannon index associated with the addition of CBM588 to nivolumab–ipilimumab were detected. Secondary endpoints included response rate, progression-free survival (PFS) and toxicity. PFS was significantly longer in patients receiving nivolumab–ipilimumab with CBM588 than without (12.7 months versus 2.5 months, hazard ratio 0.15, 95% confidence interval 0.05–0.47, P = 0.001). Although not statistically significant, the response rate was also higher in patients receiving CBM588 (58% versus 20%, P = 0.06). No significant difference in toxicity was observed between the study arms. The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments.

Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors

“… 34 , 35 It has been shown that CBM588 modulates composition of gut microbiome and increases resident Bifidobacterium in a murine model and cancer patients. 8 , 22 In consistent with the results reported by Dizman and Meza et al ., 22 our study showed that resident Bifidobacterium tends to increase in the gut of lung cancer patients who received CBM588 of the presence of C. butyricum in the gut microbiome. These lines of evidence support the hypothesis that CBM588 may have the potential to improve the therapeutic efficacy of ICB through the modulation of gut microbiota.…”

“…CBM588 has been shown to increase resident Bifidobacterium , which is known as a potentially beneficial bacteria for immunotherapy. 4 , 22 , 34 , 35 16S rRNA gene sequencing of fecal samples showed a 1.8-fold non-significant increase in Bifidobacterium in cancer patients who received CBM588 ( Figure 7(c )). Patients who received CBM588 had lesser relative abundance of potentially harmful oral-related bacteria for immunotherapy, Atopobium ( Figure 7(d )).…”

“…Recent preliminary results of clinical studies have shown the ability of live biotherapeutic bacterium to induce compositional shifts in the gut microbiome and to provide the positive impact on the clinical benefit to ICB. 4 , 20 , 22 , 42 However, the impact of CBM588 on gut microbiota in patients with thoracic cancer had remained unknown. In the current study, we found patients who received CBM588 had a lesser abundance of potentially harmful oral-related bacterial genera, Atopobium and Streptococcus , 26 , 27 suggesting that CBM588 may have the potential to shift the gut dysbiosis to a favorable microbiota.…”

“…Retrospective and prospective clinical studies have reported CBM588 significantly enhanced the efficacy of ICB, 20 , 22 however, the underlining mechanism remains unknown. Dietary fiber is fermented to butyrate by C. butyricum , 8 and the butyrate promotes the epithelial barrier function and has potent epigenetic regulatory activity.…”

“… 20 A randomized phase IB clinical trial comparing nivolumab/ipilimumab with or without CBM588 in patients with metastatic renal cell carcinoma is ongoing (NCT03829111) and the preliminary results suggested that CBM588 has the capacity to modulate the gut microbiome and enhance the response to ICB. 22 …”