Salmonella-based tumor-targeted cancer therapy: tumor amplified protein expression therapy (TAPET (TM)) for diagnostic imaging

In preclinical studies, genetically engineered Salmonella have the ability to localize, selectively accumulate, and persist within transplantable muri ne tumors, spontaneous murine tumors and human tumor xenographs, and can ex press therapeutic proteins at high levels. These strains of engineered non- virulent Salmonella typhimurium display the capacity to accumulate and grow selectively in a variety of tumor types and to inhibit the growth of prima ry and metastatic tumors following intravenous injection into tumor-bearing mice. One strain of the bacteria (VNP20009) which has endogenous antitumor activity is currently in Phase I clinical trials. The bacteria are highly attenuated and genetically stable. The combination of the lipid mutation an d the purine auxotrophy attenuate the virulence of the bacteria by greater than 10 000-fold and enhance the specificity of the bacteria for tumor tiss ue. These bacteria have been found to be safe in mice, pigs and monkeys whe n administered intravenously. Second-generation Salmonella vectors will be developed to include transgenes that will express therapeutic agents and re porter transgenes for non-invasive imaging. We have performed a preliminary study to demonstrate localization of [C-14]FIAU in tumored mice pretreated with Salmonella expressing HSVI-TK. The [C-14]FIAU radioactivity and bacte rial count data strongly support a Salmonella(TK)-dependent [C-14]FIAU accu mulation of at least 30-fold higher in tumor tissue compared to muscle tiss ue. These data warrant further investigation on the use of genetically engi neered Salmonella as a systemically administered tumor-specific agents for tumor therapy and delivery of diagnostic imaging markers. (C) 2001 Elsevier Science B.V. All rights reserved.