Oral delivery of a microbial extracellular vesicle induces potent anti-tumor immunity in mice

Abstract

Abstract The small intestinal axis (SINTAX) is a network of anatomic and functional connections between the small intestine and the rest of the body. It acts as an immunosurveillance system, integrating signals from the environment that affect physiological processes throughout the body. The impact of events in the gut in the control of tumor immunity is beginning to be appreciated. We have previously shown that an orally delivered single strain of commensal bacteria induces anti-tumor immunity via activation of innate and adaptive immunity. Some bacteria produce extracellular vesicles (EVs) that share molecular content with the parent bacterium in a particle that is roughly 1/1000th the volume in a non-replicating form. We report here an orally-delivered and gut-restricted bacterial EV which potently attenuates tumor growth to a greater extent than whole bacteria or checkpoint inhibition. EDP1908 is a preparation of EVs produced by a bacterium of the Oscillospiraceae family isolated from a human donor. Treatment of tumor-bearing mice with EDP1908 shows superior control of tumor growth compared to anti-PD-1 or an intact microbe. EDP1908 significantly increases the percentage of IFNγ producing CD8+, NK, NKT and CD4+ cells in the tumor microenvironment (TME). EDP1908 also increases tumor-infiltrating dendritic cells (DC1 and DC2) and production of IP-10 and IFNg in the TME, creating an environment conducive to the recruitment and activation of anti-tumor lymphocytes. These data point to oral EVs as a new class of immunotherapeutic drugs that harness the biology of the small intestinal axis, acting locally on host cells in the gut to control distal immune responses within the TME. EDP1908 is in preclinical development for the treatment of cancer.