Peer-Reviewed Journal Details
Mandatory Fields
Cronin, M;Le Boeuf, F;Murphy, C;Roy, DG;Falls, T;Bell, JC;Tangney, M
2014
June
Molecular Therapy
Bacterial-Mediated Knockdown of Tumor Resistance to an Oncolytic Virus Enhances Therapy
Validated
Optional Fields
ESCHERICHIA-COLI NISSLE-1917 VESICULAR STOMATITIS-VIRUS CANCER GENE-THERAPY DELIVERY VECTORS IN-VIVO SALMONELLA AGENTS TYPHIMURIUM VIROTHERAPY INDUCTION
22
1188
1197
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 VSV Delta 51 was greatly enhanced by B18R produced from E. coli. Moreover, a significant increase in therapeutic efficacy resulted from intravenous (IV) injection of bacteria to tumor-bearing mice 5 days prior to IV VSV Delta 51 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.
NEW YORK
1525-0016
10.1038/mt.2014.23
Grant Details