Metagenomic Shotgun Sequencing and Unbiased Metabolomic Profiling Identify Specific Human Gut Microbiota and Metabolites Associated with Immune Checkpoint Therapy Efficacy in Melanoma Patients

By A. Frankel, Laura A. Coughlin, Jiwoong Kim, Thomas W. Froehlich, Yang Xie, E. Frenkel, A. Koh. Neoplasia, 2017

619 citations recorded by the source corpus.

This is the first prospective study of the effects of human gut microbiota and metabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT—particularly with BRAF-wild-type disease. In preclinical studies, specific gut microbiota promotes regression of melanoma in mice. We therefore conducted a study of the effects of pretreatment gut microbiota and metabolites on ICT Response Evaluation Criteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders. Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity.

Subfields: Epidemiology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/958c7f26d0ade35c9018c6a55f1560c76503e082

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Citations in the corpus

• The microbiome and cancer (2018, background): “In an interesting aside, surveying predictors of checkpoint response from the microbial genome and metabolome, Frankel et al observed that one of the stronger associations with response was with the xenobiotic anacardic acid, which is a potential modulator of macrophage antibacterial activity, deriv”
• The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy. (2018, methodology): “However, at lower levels of taxonomy, these generalizations do not apply, as some taxa within Firmicutes have been associated with a lack of response (Roseburia, Streptococcus) (Frankel et al., 2017; Matson et al., 2018) and some taxa within Bacteroidetes have been associated with response (Alistipe”
• The microbiome and human cancer (2021, background): “Moreover, observations in humans and mice of gut microbes that stratify therapy response, particularly immunotherapy (16, 17, 21, 26), have not uncommonly shown varying taxonomic differences that persist despite uniform bioinformatic reanalyses, although there is greater concordance when examining f”