The human gut microbiome is a diverse, dynamic and complex ecosystem that modulates numerous host processes including metabolism, inflammation and cellular and humoral immune responses. Recent publications have suggested that the gut microbiota of cancer patients is predictive of response to immune checkpoint inhibitors (ICI). To better understand how the microbiome may impact response to ICI, we have developed and validated a robust tumor model using gnotobiotic mice. Germ free mice were colonized by stool transplanted from a healthy human donor, and the microbiota allowed to stabilize over several weeks. Mice were then injected with murine syngeneic tumor cells. When tumors reached the appropriate size, mice were treated with either control antibody or anti-PD-1 antibody, and tumor growth response was monitored over time. At the end of study mice were sacrificed, and tumors and tumor draining lymph nodes were collected for analyses of immune infiltrating cells by flow cytometry. Germ free mice (not colonized with any microbiota) were used as controls. Similar studies were also performed using only the spore fraction of donor stool. Our data demonstrated that tumor responsiveness to anti-PD-1 treatment was significantly greater in the germ-free mice colonized with either healthy donor stool or the spore only composition, as compared to control mice. This response was accompanied by an increased infiltration of activated CD8+ T cells into the tumor. In addition, analyses of immune cells in the colon provided a window into the activation of the immune system and T cell trafficking induced by human microbes in gnotobiotic mice. Fecal pellets from the colonized mice were sequenced for 16S rDNA to identify “microbial signatures” associated with response to ICI treatment.

Based on these encouraging animal model data we plan to initiate a randomized, placebo-controlled clinical study at MD Anderson Cancer Center in 2018, sponsored by the Parker Institute for Cancer Immunotherapy, in patients with advanced metastatic melanoma. The clinical trial will evaluate the impact of an anti-PD-1 checkpoint inhibitor with adjunctive microbiome therapy on patient outcomes. Seres is developing SER-401, a preclinical stage oral microbiome therapy to improve the efficacy and safety of immunotherapy. Our drug discovery strategy iterates computational analyses with machine learning approaches, as well as empirical in vitro, in vivo and ex-vivo screening of strains and consortia to inform selection and drive microbiome drug design. Data from such a comprehensive approach is invaluable for designing compositions of bacteria that form “functional ecological networks” that can impact response to ICI therapy. We believe these data will provide insight into how microbiome drugs can be discovered and developed in the setting of immunotherapy to augment the efficacy of ICIs by altering the cancer-immune set point.

Citation Format: Jaclyn Sceneay, Srimathi Srinivasan, Keith Halley, George Marnellos, Jennifer Wortman, Matthew Henn, Elura Fink, Kevin Litcofsky, David Cook, Lata Jayaraman. Leveraging gut microbiota networks to impact tumor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-283.