GENETIC IMPROVEMENTS OF TUMOR-TARGETED SALMONELLA

DESCRIPTION (provided by applicant): Salmonella are under development as anticancer vectors. In mice, attenuated Salmonella injected intravenously or intratumorally multiply preferentially within tumors, suppress tumor growth and prolong survival. One strain, VNP20009, is currently in human Phase I clinical trials. A key mutation in VNP20009, a partial deletion of the msbB gene which renders the bacterial endotoxin virtually incapable of eliciting septic shock, also makes the bacteria sensitive to a variety of salt and chelating agents, generally limiting the growth of the bacteria under certain conditions. Spontaneously arising strains with compensatory mutations were previously isolated which included VNP20009, and their antitumor activity determined. Growth properties of these strains were partially restored, but their efficacy ranged from little or no antitumor activity in one strain, to those such as VNP20009 with a high degree of antitumor activity. Thus, these compensatory mutations are both diverse and important for efficacy of antitumor strains. Recently, by applying alternate selection techniques and a broader spectrum of physiological assays, a much wider diversity of spontaneous compensatory mutations which restore resistance to part or all of these sensitivities were isolated. Thus, because the broad spectrum of compensatory mutations was only recently recognized, only a few of these have been tested for antitumor activity thus far. Here, we propose to isolate this broad spectrum of compensatory mutants using transposon mutagenesis and to move these insertions into tumor-selective strains, thereby generating new antitumor strains with the potential for improved properties. These new strains of Salmonella with compensatory mutations will be tested for antitumor activity. PROPOSED COMMERCIAL APPLICATIONS: Highly selectie bacterial vectors working directly at diseased sites throughout the body offer the potential to eradicate diseased tissue with substantially reduced side effects due to non-specific toxicity. We anticipate that patients with untreatable and inaccessible metastatic and solid tumors will be the primary markets. The first Salmonella vector, VNP20009, is already in human phase I clinical trials for treatment of solid tumors.