Lipid A mutant Salmonella with suppressed virulence and TNF alpha induction retain tumor-targeting in vivo

Systemically administered tumor-targeted Salmonella has been developed as a n anticancer agent, although its use could be limited by the potential indu ction of tumor necrosis factor alpha (TNF alpha)-mediated septic shock stim ulated by lipid A. Genetic modifications of tumor-targeting Salmonella that alter lipid A and increase safety must, however, retain the useful propert ies of this bacteria. We report here that disruption of the Salmonella msbB gene reduces TNF alpha induction and increases the LD50 of this pathogenic bacteria by 10,000-fold, Notwithstanding this enormous difference, Salmone lla retains its tumor-targeting properties, exhibiting tumor accumulation r atios in excess of 1000:1 compared with normal tissues. Administration of t his bacteria to mice bearing melanoma results in tumors that are less than 6% the size of tumors in untreated controls at day 18. Thus, the antitumor activity previously demonstrated using tumor-targeting Salmonella with norm al lipid A is retained. Lipid modification of tumor-specific bacterial vect ors provides a means for reducing septic shock and further suggests that th e antitumor activity of these bacteria may be independent of TNF alpha.