Engineered Salmonella for drug delivery to solid tumors.

Engineered bacteria have the potential to overcome the limitations that cause cancer therapies to fail. We are engineering bacteria to deliver therapeutic payloads and quantifying the mechanisms that control bacterial therapy. We have shown that bacteria preferentially target tumors and actively penetrate tissue. Bacterial motility has a linear relationship with colonization density. Manipulating chemoreceptors in the membrane can direct bacteria to drug-resistant tumor regions, and inducing inflammation can promote colonization by modifying tumor vasculature. When engineered to express α-hemolysin from Staphylococcus aureus, bacteria kill 99% of culture cells in 5 minutes and reduce tumor volume in mice. Engineering Salmonella with quorum-sensing provides a density-dependent switch that induces protein expression only after bacteria have colonized tumor tissue. This technique prevents system toxicity after delivery of therapeutic molecules. We have also developed bacteria that selectively invade cancer cells and release molecules that modulate epigenetic targets, e.g., EZH2 and PP1. Salmonella were engineered with a genetic cassette that induces lysis specifically after invasion into mammalian cells. Lysis releases the bacterial content into the cytoplasm of cells. In culture, Salmonella lyse inside cancer cells and release GFP, which diffuses throughout the cellular cytoplasm. Releasing a peptide that interferes with the binding of the phosphatase, PP1, with its regulator, NIPP1, induces cell death after bacterial lysis. In three-dimensional tissue culture, administration of these bacteria induces cell death. These techniques establish Salmonella as a tunable platform for cancer therapy. By understanding the mechanisms of bacterial delivery, new strategies will be developed to treat hard-to-treat cancers. Citation Format: Neil S. Forbes. Engineered Salmonella for drug delivery to solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA24.