The human gut microbiota forms a diverse, dynamic and complex ecosystem that modulates numerous host processes including metabolism, inflammation and cellular and humoral immune responses. Emerging data suggest that the gut microbiota of cancer patients may predict tumor response to immune checkpoint inhibitors (ICI). To better understand how the microbiome may impact response to ICI, we have developed and validated robust tumor models using either conventional mice treated with antibiotics or germ-free (GF) mice. We have confirmed in both models, that mice lacking a diverse microbiome fail to mount an efficient anti-tumor immune response after treatment with anti-PD-1, primarily due to T cell dysfunction. This response to anti-PD-1 can be restored by introduction of a microbiome using fecal microbial transplant (FMT) prepared from stool from healthy donors in GF mice, and is driven by increased tumor-infiltrating lymphocytes (TILs), specifically CD8+ T cells. Importantly, for the first time, we show that the bacterial spore fraction from healthy donor stool can also restore response to anti-PD-1 and increase CD8+ TILs in both conventional mice treated with antibiotics and GF mice. We have also tested cancer patient-derived microbiome samples that are efficacious or non-efficacious in GF mouse models. We have sequenced the input material as well as the engrafted gut microbiota in these mice via 16S rDNA sequencing. Comparison of these sequences has enabled us to develop a “microbiome signature” of response that is being used in the development of a microbiome-based therapy for combination with ICI. Based on these encouraging animal model data we plan to initiate a randomized, placebo-controlled clinical study 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 combines computational analyses and 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 are 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 developed in the setting of immunotherapy to augment the efficacy of ICIs by altering the cancer-immune set point.
Citation Format: Lata Jayaraman, Jaclyn Sceneay. Leveraging gut microbiota networks to impact tumor immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2839.