Development of Salmonella for cancer therapeutics

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Salmonella enterica serovar Typhimurium (Salmonella) is an extensively studied model pathogen. This facultative intracellular pathogen actively invades non-phagocytic host cells, such as intestinal epithelial cells, using a Type III Secretion System that delivers a cohort of bacterial effector proteins across the plasma membrane. Salmonella have also been shown to colonize solid tumors and are considered a leading contender for the development of bacterial-mediated anti-tumor therapy. Live recombinant attenuated Salmonella can be used to deliver proteins, DNA plasmids or other molecules directly to solid tumors or the tumor microenvironment. Salmonella can be delivered orally, are inexpensive to produce and can elicit both mucosal and systemic immune responses. Our goal is to engineer a safe attenuated strain to target solid tumors either alone or in combination with other treatments such as chemotherapy or immunotherapy. For the initial screening and strain development, we are using a melanoma model in which B16 melanoma cells are inoculated in the syngeneic C57BL6J mouse strain. We have established this solid tumor model in both WT C57BL6J mice and Nramp1 (SLC11A1) reconstituted C57BL6J mice, which are more resistant to Salmonella. We found that, in both backgrounds B16 tumors are highly colonized following infection with Salmonella Typhimurium VNP20009, an attenuated strain that has been tested in several tumor models, or attenuated SL1344, a widely used laboratory strain that we have extensive experience with. Both strains inhibit tumor growth even in the absence of an anti-cancer payload. We have developed an environmental sensor system to trigger bacterial lysis specifically in the tumor microenvironment. To assess the impact of these bioengineered strains on tumors we have assessed immune cell recruitment using flow cytometry and immunohistochemistry.