In a randomised, open-label, single-centre study, a bifidogenic live bacterial product CBM588 augmented response to immune checkpoint inhibitors through modulation of the gut microbiome. CBM588 enhanced the clinical outcome in patients with treatment-naïve metastatic renal cell carcinoma (mRCC) treated with nivolumab–ipilimumab combination. Larger studies are warranted to confirm this clinical observation and elucidate the mechanism of action and the effects on microbiome and immune compartments, according to Prof. Sumanta K. Pal of the Department of Medical Oncology, City of Hope Comprehensive Cancer Center in Duarte, CA, USA and colleagues, who published the study findings on 28 February 2022 in the Nature Medicine.
The study team wrote in the background that multiple groups have independently demonstrated a link between the gut microbiome and response to immunotherapy in patients with cancer. For example, in patients with mRCC and non-small cell lung cancer (NSCLC), evaluation of the baseline stool microbiome profile prior to initiation of immune checkpoint inhibitors identified multiple species, most notably Akkermansia spp. that were associated with enhanced response rate and prolonged progression-free survival (PFS). In patients with mRCC the species such as Bifidobacterium adolescentis and Barnesiella intestinihominis were associated with enhanced clinical benefit from immune checkpoint inhibitors. Other studies also support the role of Bifidobacterium spp. in the modulation of response to immune checkpoint inhibitors. In preclinical models, transplantation of foecal material enriched with Bifidobacterium spp. alone, even without immune checkpoint inhibitors, was sufficient to delay tumour growth.
Majority of patients with mRCC who receive nivolumab-ipilimumab combination regimen do not achieve a response and approximately 20% of patients have immediate progression of their disease on this regimen. These results prompted prospective investigation of whether modulation of the gut microbiome could enhance the response to nivolumab–ipilimumab in patients with mRCC. The live bacterial product CBM588 contains Clostridium butyricum, a butyrate-producing anaerobic spore-forming bacterium. In preclinical studies, the agent appeared to be bifidogenic. A retrospective study in patients with NSCLC who received immune checkpoint inhibitors showed a profound impact of CBM588 on both PFS and overall survival. The benefit of CBM588 appeared to be more pronounced in patients who had received antibiotic therapy, a striking finding given that antibiotics have consistently been shown to diminish the impact of immune checkpoint inhibitors.
Based on these observations, the study team designed a randomised study to test prospectively the effects of CBM588 in patients with mRCC treated with nivolumab–ipilimumab. The study primary endpoint was the characterisation of the effect of the agent on the relative abundance of gut microbial populations and specifically Bifidobacterium spp. Secondary endpoints included response rate, PFS and toxicity.
In this open-label, single-centre phase I study, 30 treatment-naive patients with mRCC with clear cell and/or sarcomatoid histology and intermediate- or poor-risk disease were randomised 2:1 to receive nivolumab-ipilimumab with or without daily oral CBM588. 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. Although the primary endpoint was not formally met, subgroup analyses showed an increase in Bifidobacterium spp. in patients who responded to CBM588 in combination with nivolumab–ipilimumab.
In terms of secondary endpoints, PFS was significantly longer in patients treated with 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 results of this randomised clinical study suggest that supplementation with live bacterial products may augment the activity of immune checkpoint inhibitors. Perhaps more importantly, the efficacy analyses highlighted a significant improvement in PFS with the addition of CBM588 to nivolumab–ipilimumab. Although this must be cautiously interpreted given the small sample size, consistent results were obtained favouring CBM588 in analyses of response rate. Although no significant change in Bifidobacterium spp. was observed with CBM588 therapy, an increase in these organisms was specifically observed in responders.
This study faces the challenge of other projects in the microbiome space. Despite these limitations, it is important to validate these findings in larger series and across different tumour types.
Funding for the study was provided by a grant from the Gateway for Cancer Research. CBM588 was supplied by Miyarisan Pharmaceuticals Co., Ltd. and OSEL, Inc.
Association of microbial signatures with clinical response and immune-related adverse effects in patients with melanoma treated with anti-PD1 therapy
In another study published also on 28 February 2022 in the Nature Medicine, the reserchers from the Cancer Immunobiology Section, Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute (NCI) in Bethesda, MD, USA reported findings from an integrated analysis of microbiome and host cell transcriptional data on clinically annotated cohorts of patients with melanoma who were treated with anti-PD1 therapy. The analysis uncovered new associations of Streptococcus species with immune-related adverse effects and showed consistent microbiome associations with clinical outcomes.
The authors wrote that the gut microbiome is a tumour-extrinsic factor associated with antitumour response to anti-PD1 therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, they evaluated a new melanoma cohort, along with four published datasets.
Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data showed that bacteria associated with favourable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavourable outcome.
Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favourable and unfavourable clinical response and with distinct immune-related adverse effects.
Despite heterogeneity between cohorts, optimised supervised learning algorithms consistently predicted outcomes to anti-PD1 therapy in all cohorts. Gut microbial communities with non-uniform geographical distribution were associated with favourable and unfavourable outcomes, contributing to discrepancies between cohorts.
This work was supported in part by NCI and other non-profit and academic institutions.
- Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nature Medicine; Published online 28 February 2022. DOI: https://doi.org/10.1038/s41591-022-01694-6
- McCulloch JA, Davar D, Rodrigues RR, et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nature Medicine; Published online 28 February 2022. https://doi.org/10.1038/s41591-022-01698-2