Altering Gut Microbiome May Improve ICI Outcomes in RCC

A new study suggests that interventions to modulate the composition of the gut microbiome may be one way to boost the effectiveness of immune checkpoint inhibitors (ICIs) in patients with renal cell carcinoma (RCC). It is the largest prospective analysis to date looking at the connection between ICIs and gut microbiome, according to the investigators. Lisa Derosa, from the Gustave Roussy Cancer Campus, Paris Saclay University, Villejuif, France, and colleagues reported the findings in a poster presentation (abstract 4519) at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago

Derosa and colleagues believe the composition of gut microbiome may predict resistance to anti–programmed death 1 (PD-1) in RCC patients. They theorize that interventions to modulate the gut microbiome composition may represent novel strategies to improve clinical outcomes with ICIs in this population.

It is unknown what mechanisms are driving response/resistance to ICIs. In their investigation, Derosa et al evaluated the individual gut microbiome, to test their hypothesis that dysbiosis resulting from use of antibiotics decreases the activity of ICIs in patients with cancer. The researchers note that previous studies in melanoma and in epithelial cancers found outcomes of ICI therapy were influenced by patients’ microbiome composition.

The current investigation included 85 patients with RCC who were treated with nivolumab in the NIVOREN study. Derosa et al prospectively collected fecal samples from 69 patients. Among these 69 patients, 11 had received antibiotics before starting ICIs. The investigators classified patients as having either primary ICI-resistant disease (PD) or non-PD, based on RECIST (Response Evaluation Criteria in Solid Tumors; outcome, 6 months PFS).

The team also employed metagenomic (MG) data from whole genome sequencing (WGS) into their multivariate models. To establish a cause-and-effect relationship between dysbiosis and resistance, the researchers used animal models. ICI-resistant mice were compensated with fecal microbiota transplantation (FMT) from non-PD patients, to restore responsiveness to ICIs.

The study showed that after a median follow-up of 14 months, 39% of the patients (n = 27) were PD and 61% (n = 42) were non-PD, based on best response. When the investigators evaluated patients who received antibiotics, 73% were PD (n = 8) and 27% were non-PD (n = 3; P = .01). The study showed that the microbiome alfa (intra-sample) and beta (inter-sample) diversity were not significantly different between PD and non-PD RCC patients. However, specific gut MG-fingerprints were related to best responses and/or progression free survival (PFS).

Derosa and colleagues found that when antibiotic-using patients were excluded, Akkermansia muciniphila and Bacteroides salyersiae were more abundant in non-PD patients. They then showed that Bacteroides (B. salyersiae but not B. xylanisolvens) or A. muciniphila could restore the efficacy of ICI in a patient with unfavorable/dysbiotic status in a significant number of cases.