The role of the intestinal microbiome in cancer immunotherapy

ABSTRACT The gut microbiota consists of a community of diverse microbes and has many effects on human (patho)physiology. Microbiome composition has been associated with many diseases, but causal inference is often lacking. Preclinical and clinical studies have demonstrated that the intestinal microbiota can regulate innate and adaptive immunity, including T cell and antitumor immunity after allogeneic hematopoietic cell transplantation (allo-HCT) and checkpoint blockade. My lab has focused on the role of gut microbiota in outcomes of allo-HCT and immunotherapy. For example, we showed that microbiota composition undergoes significant and frequent changes during allo-HCT and that lower intestinal microbiota diversity is associated with increased mortality. We also found that dominance by certain species, most frequently Enterococcus, is associated with lethal graft-versus-host disease (GVHD); that exposure to certain antibiotics is associated with worse outcomes following allo-HCT and chimeric antigen receptor T cell (CART) therapy; and that hematopoietic reconstitution is associated with the presence of beneficial flora. These studies have been translated into clinical trials using autologous fecal microbiota transplant, administration of defined bacterial consortia, and antibiotic stewardship to spare and/or restore the commensal flora. The overarching hypothesis of this proposal is that the intestinal microbiome is an important modulator of innate and adaptive immunity in the setting of cancer immunotherapy. While immunotherapies are curative in some recipients, improving their efficacy and abating toxicities are unmet needs in oncology. The major goals are to improve cancer immunotherapy by targeting the intestinal microbiome based on preclinical and clinical studies. Examples of our ongoing and planned studies include: a) development of a new pipeline for microbiome analysis, b) preclinical and clinical projects regarding intestinal microbiome and CART, c) new techniques to analyze the effects of diet and drugs on the intestinal microbiome, and d) preclinical and clinical studies regarding immune modulation by bile acids, as an example how we study the mechanisms by which the intestinal microbiome can modulate immunity and cancer immunotherapy. We have organized a multicenter global consortium to collect fecal samples (funded separately from this application) along with a novel multi-omic approach to integrate patient, microbiome, and tumor profiling modalities using a computational platform (MSK-MIND) for data harmonization and machine learning. These investigations will be performed via perpetual dialogue between work with mice and humans: human studies enable us to observe correlations, develop hypotheses, and test therapeutic strategies; animal studies enable us to establish or refute causal relationships between microbiota and host immunology and to obtain mechanistic insights. These data will inform the future development of clinical trials to test therapeutic strategies to enhance efficacy and decrease toxicity in patients receiving cancer immunotherapy, such as CART and allo-HCT.