Attenuated Salmonella VNP20009 mutant (ΔhtrA) is a promising candidate for bacteria‐mediated tumour therapy in hosts with TNFR1 deficiency.

Abstract: VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anticancer effect wildly used in tumour therapy on animal models. For its clinical application, an accurate bio‐safety assessment on sensitive models is necessary. In this study, we use TNFR1 KO mice as a susceptive model to assess the virulence of bacterial VNP20009 and its derivative ΔhtrA. By intraperitoneal administration of Salmonella, the increased lethality was observed in TNFR1 KO mice infected with VNP20009, but not with ΔhtrA. We performed a systemically comparative analysis of their toxicity, and ΔhtrA shows a better bio‐safety for TNFR1 KO mice. Since the macrophages with TNFR1 deficiency exhibit a reduced ability of bacteria clearance, ΔhtrA with lower survival ability in normal macrophages restores its viability in TNFR1 KO macrophages. Thus, ΔhtrA was further tested for its antitumour effect in TNFR1 KO mice bearing a B16F10 melanoma model. It displays a moderate antitumour effect, suggesting ΔhtrA instead of VNP20009 might be a promising candidate for bacteria‐mediated tumour therapy specific to those with low immunity. Significant and Impact of the Study: VNP20009 is attenuated Salmonella with a good safety widely used for tumour‐targeting bacterial therapies. Little is known about its toxicity in hosts with low immunity. This study is the first systemically comparative analysis of their toxicity of VNP20009 and its mutant ΔhtrA in TNFR1‐KO mice. Research on toxicity of tumour‐targeting Salmonella in mice with immunodeficiency can facilitate the optimization of bacterial therapies with reduced adverse effects in future clinical trials. [ABSTRACT FROM AUTHOR]