Abstract 1422: A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor therapy

Abstract

Abstract Immune checkpoint inhibitor therapy (ICT) has revolutionized cancer care, but up to 50% of patients do not respond to ICT. A host factor implicated in variable ICT response is the gut microbiome: a) germfree/antibiotic-treated mice do not respond to ICT; b) human ICT responders have distinct gut microbiome signatures compared to non-responders; and c) fecal microbiota transplants are safe and potentially effective in cancer patients previously unresponsive to ICT. We have previously established that ICT induces translocation of gut microbiota into secondary lymphoid tissues (particularly the mesenteric lymph nodes) and tumor which is required to enhance extraintestinal anti-tumor immunity (PMID: 36867675). Here, we have developed a novel gut microbiota therapy (GMT) which circumvents the challenges and limitations of conventional microbiome therapies that use live microbes. GMT utilizes specific components derived from commensal gut microbiota identified in our published clinical study (PMID:28923537) that can be administered parenterally (subcutaneous/intravenous) to safely and reproducibly enhance ICT efficacy in multiple preclinical cancer models (B16-F10 with anti-PD-1 and/or CTLA-4, MC38 with or without anti-PD-1, humanized mouse with human melanoma and human anti-PD-1). GMT acts by agonizing the pattern recognition receptors hTLR1/2/6, hNOD2 and hSTING. GMT induces anti-tumor cytokines (IL-12) but does not significantly increase sepsis associated cytokines (IL-6, TNFa) in both human immune cells and in non-human primates. Mechanistically, GMT acts via dendritic cells, and potentially through increased expression of delta-like ligand protein 4 (DLL4), a Notch signaling ligand that activates Notch 1/4 in T cells and promotes Th1 and Th17 differentiation. Current efforts to identify the active components of GMT are underway in which we have used serial liquid-liquid extractions (ethyl acetate followed by water:methanol:chloroform) and subsequent reverse phase chromatography to identify the most active fractions and identification of the bacterial components/constituents within these fractions. Together, these results demonstrate that GMT has the potential to serve as an innate immune adjuvant (akin to vaccine adjuvants) that enhances the effect of immunotherapy for possibly many cancer types. Citation Format: Priscilla Del Valle, Gabriella Nguyen, Yongbin Choi, Parastoo Sabaeifard, Wenng li, Jake Lichterman, Laura Coughlin, Nicole Poulides, Angelica Sanjuan, Andrew Y. Koh. A novel gut microbiota therapeutic approach for enhancing immune checkpoint inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1422.