REDUCED TOXICITY OF TUMOR-TARGETED SALMONELLA

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DESCRIPTION: Phase I: This application focuses on development of novel nonpathogenic bacterial vectors for targeting solid tumors. The investigators have engineered attenuated Salmonella vectors which, following systemic administration into tumor-bearing mice, replicate over four orders of magnitude within tumors, with minimal replication in adjacent normal tissues. Initial studies have shown that this method is effective at both slowing tumor growth and prolonging survival, and is applicable to the treatment of a variety of cancers, including lung, breast, liver, kidney, colon and melanoma. These vectors were attenuated by auxotrophic mutations which limit their pathogenesis in normal tissues. A further concern for the in vivo use of bacteria is their ability to induce tumor necrosis factor-alpha (TNF-alpha)-mediated septic shock. The investigators have now isolated a mutation in Salmonella which alters the lipid A coat, thereby reducing TNF-alpha induction, yet retains the tumor- targeting and antitumor activity of these bacteria in vivo. In order to develop strains of bacteria that are devoid of septic shock and are fully attenuated, investigators propose to explore the use of this lipid mutation in combination with auxotrophic mutations to generate a variety of auxotrophies which will be tested for tumor-targeting and antitumor activity in at least two solid tumor models. These studies will result in fully attenuated Salmonella vectors with potent antitumor activity capable of targeting both the primary tumors and metastatic sites. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE