Cronin Michelle, Le Boeuf Fabrice, Murphy Carola, Roy Dominic G, Falls Theresa, Bell John C, Tangney Mark
Cork Cancer Research Centre, University College Cork, Cork, Ireland.
Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Mol Ther. 2014 Jun;22(6):1188-1197. doi: 10.1038/mt.2014.23. Epub 2014 Feb 26.
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.
溶瘤病毒（OVs）和细菌在全身给药后具有肿瘤选择性复制的特性。对于非致病性细菌而言，肿瘤选择性与其在肿瘤基质中细胞外生长的能力有关，因此非常适合将细菌产生的治疗剂的产生限制在肿瘤内。我们之前已经证明1型干扰素拮抗剂B18R能够通过克服相关的细胞固有免疫来增强水疱性口炎病毒（VSV）的复制和传播。在本研究中，我们利用表达B18R的非致病性细菌（大肠杆菌）来促进B18R在肿瘤中的特异性产生，从而形成一个生物活性抗病毒细胞因子匮乏的微环境，从而“预处理”肿瘤以增强随后OV对肿瘤的破坏作用。由大肠杆菌产生的B18R极大地增强了VSVΔ51在体外和体内的感染。此外，在静脉注射VSVΔ51前5天向荷瘤小鼠静脉注射细菌，治疗效果显著提高，表现为小鼠肿瘤生长显著减缓且存活率增加。我们的策略是首次将两种如此不同的微生物进行合理组合的例子，证明了组合互补微生物以改善治疗效果的可行性。
