Figure 3.

(A) Viral inoculation results in the infection of cancer cells and surrounding non-neoplastic tissue; however, only cancerous cells will support active viral replication. Just hours following viral inoculation, the tumor microenvironment undergoes a series of dynamic changes (B) that create a barrier for efficient viral replication and spread: (i) an angiogenic response with vasodilation and leakage of inflammatory cellular responders; (ii) elaboration of inflammatory cytokines that create an environment that is limiting for viral replication; (iii) the recruitment and activation of cells from the innate immune system; (iv) components of the ECM create an environment with high interstitial pressure that limits viral dissemination between individual cancer cells. If these responses to viral infection are not addressed, viral clearance will be seen within days of viral administration with limited tumor killing (C); however, each component of the host responses also provides a drug target that can be used to enhance OV efficacy using cotherapy. By tailoring OV therapy with pharmacologic agents, viral replication and spread can be enhanced with increased tumor killing (D).