Augmenting Metastatic RCC Immunotherapy with Gut Microbiome Modulation

A recently published study in Nature Medicine by Nazli Dizman and colleagues1 reports on a preliminary phase 1 clinical trial offering promising early results for gut microbiome modulation in immunotherapy.

Immunotherapy for advanced (stage 4 or greater) can be broadly classified into checkpoint inhibitor therapy or combinations of checkpoint inhibitors and antiangiogenic compounds. Checkpoint inhibitors typically target the programmed cell death receptor 1 (PD-1) pathway or the cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway, whereas antiangiogenic compounds typically target the vascular endothelial growth factor pathway. The authors investigated a combination of therapeutic compounds that are both checkpoint inhibitors: nivolumab (NIVO; OpdivoÒ, Bristol Myers Squibb), which targets the PD-1 axis, and ipilimumab (IPI; YervoyÒ, Bristol Myers Squibb), which targets the CTLA-4 axis.

Prior clinical trials have documented the combined benefit of NIVO plus IPI (NIVO+IPI) and its ability to provide enhanced cytotoxic T-cell function that improves antineoplastic responses in metastatic RCC. Indeed, the latest kidney cancer guidelines from the National Comprehensive Cancer NetworkÒ recommend NIVO+IPI as the preferred first-line therapy for patients with poor- and intermediate-risk metastatic clear cell RCC.2

The US Food and Drug Administration approved this therapy combination in April 2018,3 supported primarily by the phase 3 CheckMate 214 clinical trial initially presented at the 2015 meeting of the American Society of Clinical Oncology.4 In CheckMate 214, patients were randomized to receive either NIVO+IPI therapy or sunitinib therapy (control).6 The investigators reported a median progression-free survival (PFS) of 11.6 months compared with 8.4 months in the control arm. Most notably, there was a 42% objective response rate (ORR) in the experimental arm, compared with 27% in the control arm, resulting in an 18-month overall survival (OS) rate of 75%. More recently, the investigators presented 30-month follow-up data demonstrating a persistent OS advantage of 34% (hazard ratio, 0.66; 95% CI, 0.54-0.80).5

Despite these promising findings, Dizman et al remarked that the CheckMate 214 results demonstrate that most patients do not achieve a response, and some continue to have disease progression, highlighting the importance of seeking mechanisms to enhance the effects of immunotherapy.

The bacterial product used in their study, CBM588 (a live strain of Clostridium butyricum; Miyarisan Pharmaceutical Co., Ltd.) is thought to be “bifidogenic” (ie, stimulates growth of bifidobacteria in the intestines). In her Twitter page (@NazliDizman) question-and-answer thread, Dizman explains, “Clostridum butyricum produces high amounts of short chain fatty acids in the gut lumen and create a bifidogenic microenvironment in-vivo.” She and her colleagues point out that several other studies have suggested a link between the gut microbiome and response rates to immunotherapy, specifically with checkpoint inhibition therapy. They note that retrospective series have demonstrated improved PFS and OS with CBM588 in patients with non-small cell lung cancer receiving checkpoint inhibitors. Their phase 1 trial was created to characterize the efficacy of CBM588 in patients with advanced renal cell carcinoma receiving NIVO+IPI.

A total of 30 patients were recruited into the trial between April 2019 and December 2020, 29 of whom met the final inclusion criteria. The median age of the overall cohort was 66 years, and most patients were male. Most patients had clear cell histology, and sites of metastatic disease included lung, lymph nodes and bone. Dizman remarked that “baseline patient characteristics were similar across arms.” Patients were randomized to NIVO+IPI plus CBM588 (n=19) or NIVO+IPI alone (n=10), and were followed for a median of 12.2 months, until April 15, 2021. At the time of data cutoff, most patients were alive (n=24). Primary outcomes were relative abundance of Bifidobacterium species at baseline and at 12 weeks; secondary outcomes included response rate, PFS, and evaluation of toxicity.

Results from Gut Microbiome Modulation

Patients were asked to submit baseline and week 12 stool samples; 3 patients failed to submit samples at week 12, resulting in a total of 52 samples. Analysis of the samples failed to demonstrate any significant change in the abundance of Bifidobacterum species in either treatment arm. However, subgroup analysis of patients receiving NIVO+IPI plus CBM588 who responded to treatment revealed a significant increase in Bifidobacterium species. Metabolic pathway analysis of patients between baseline and week 12 noted upregulation of pyrimidine ribonucleotide degradation pathways, among others. On Twitter, Dizman explained that overall, they saw an “increase in metabolic pathways associated with short-chain fatty acid biosynthesis and [a] decrease in glycolytic dependence and pathogenic E. coli function.”

Analysis of the phase 1 data revealed a significantly prolonged PFS in patients receiving NIVO+IPI plus CBM588 compared with NIVO+IPI alone (12.7 vs 2.5 months). More than 50% (11 of 19) of patients in the CBM588 arm achieve an objective response compared to just 20% (2 of 10) of patients in the control arm, with measurable decreases in target lesions in 74% of individuals in the experimental arm and 50% in the control arm. On Twitter, Dizman cited an impressive ORR in the experimental arm compared with the control arm (58% vs 20%; P=0.06). The authors remarked that these preliminary results “support further evaluation of CBM588 in larger investigations.”

The safety investigation found a similar rate of adverse events in both arms (52% for NIVO+IPI plus CBM588 vs 50% for NIVO+IPI alone). The researchers also analyzed levels of circulating cytokines and immune cell populations by collecting blood samples at intervals of treatment and used baseline and week 12 samples for the analysis. They found an increase rise in CXCL9 levels in both treatment arms and noted that several specific cytokines (eg, granulocyte colony-stimulating factor) were elevated in the experimental arm (see figure 4 in the published report1).

The results of this phase 1 trial add to a growing body of literature exploring the utility of intestinal microbiome modulation in patients receiving immunotherapy. The authors remarked that, in comparison to CheckMate 214, their study demonstrated a significant advantage in PFS and a trend for improved OS. Moreover, they remarked that although ORRs in their phase 1 trial were lower (control arm, 22% vs 46% in CheckMate 214), their patient population had a greater proportion of individuals with bony metastatic disease and other adverse factors than did the CheckMate 214 study sample. Another point of note is that patients in CheckMate 214 were not restricted from consuming bacteria-filled foods, such as yogurt, whereas the phase 1 trial control arm was prohibited these foods; the authors postulate that this difference may have influenced the microbiome composition. Overall, Dizman et al concluded that addition of CBM588 may enhance the clinical outcomes of patients with metastatic renal cell carcinoma treated with NIVO+IPI and warrants further investigation.


  1. 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. [Online ahead of print.] Nat Med. 2022;10.1038/s41591-022-01694-6. doi:10.1038/s41591-02201694-6
  2. National Comprehensive Cancer NetworkÒ. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesÒ): Kidney Cancer. Version 4.2022. December 21, 2021. Accessed March 15, 2022.
  3. US Food and Drug Administration website. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. April 16, 2018. Accessed March 15, 2022.
  4. Hammers HJ, Plimack ER, Sternberg C, et al. CheckMate 214: a phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2015;33(15 suppl): abstract TPS4578. doi: 1200/jco.2015.33.15_suppl.tps4578
  5. Tannir NM, Frontera OA, Hammers HJ, et al. Thirty-month follow-up of the phase III CheckMate 214 trial of first-line nivolumab+ ipilimumab (N+ I) or sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37 (7 suppl): abstract 547. doi: 10.1200/JCO.2019.37.7_suppl.547
  6. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126