title: Bacterial-mediated knockdown of tumor resistance to an oncolytic virus enhances therapy.
abstract: Oncolytic viruses (OVs) and bacteria share the property of tumor-selective replication following systemic administration. In the case of nonpathogenic bacteria, tumor selectivity relates to their ability to grow extracellularly within tumor stroma and is therefore ideally suited to restricting the production of bacterially produced therapeutic agents to tumors. We have previously shown the ability of the type 1 interferon antagonist B18R to enhance the replication and spread of vesicular stomatitis virus (VSV) by overcoming related cellular innate immunity. In this study, we utilized nonpathogenic bacteria (E. coli) expressing B18R to facilitate tumor-specific production of B18R, resulting in a microenvironment depleted of bioactive antiviral cytokine, thus "preconditioning" the tumor to enhance subsequent tumor destruction by the OV. Both in vitro and in vivo infection by VSVΔ51 was greatly enhanced by B18R produced from E. coli. Moreover, a significant increase in therapeutic efficacy resulted from intravenous (i.v.) injection of bacteria to tumor-bearing mice 5 days prior to i.v. VSVΔ51 administration, as evidenced by a significant reduction in tumor growth and increased survival in mice. Our strategy is the first example where two such diverse microorganisms are rationally combined and demonstrates the feasibility of combining complementary microorganisms to improve therapeutic outcome.
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Michelle
authors.initials: M
authors.lastname: Cronin
authors.affiliation: Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Boeuf
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland.
authors.forename: Carola
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Dominic G
authors.initials: DG
authors.lastname: Roy
authors.affiliation: Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: Theresa
authors.initials: T
authors.lastname: Falls
authors.affiliation: Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.affiliation: Cork Cancer Research Centre, University College Cork, Cork, Ireland. Electronic address: m.tangney@ucc.ie.
authors.forename: Mark
authors.initials: M
authors.lastname: Tangney
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000382:microbiology / Q000473:pathology* / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D007275:Injections, Intravenous; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D018116:Vesiculovirus / Q000235:genetics* / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D014764:Viral Proteins; C067853:B18R protein, Vaccinia virus