**2. Switching on the Ignition with Oncolytic Viruses**

Through natural tropism, or genetic engineering, oncolytic viruses are a class of viruses which share a preference for replication in malignant cells over normal tissue. A broad diversity of viruses has been defined as having oncolytic properties and possess distinct genomes (RNA and DNA), entry specificities, replication mechanics, immuneevasion machinery, and genetic modifications which collectively confer tumour specificity. Infection of tumour cells can be facilitated by the overexpression of viral binding and entry receptors, such as CD46 for measles [31] or ICAM-1 for Coxsackievirus A21 [32]. Deletion of viral genes, complemented by high level expression in tumour cells, such as those involved in nucleotide metabolism (thymidine kinase, ribonucleotide reductase, uracil DNA glycosylase) has been employed with herpes simplex virus (HSV) and vaccinia virus (VACV) strains [33–36]. The adenovirus E1A protein binds the cellular retinoblastoma protein to drive S-phase entry, allowing it to access the cellular DNA replication and protein synthesis machinery, and a 24 amino acid deletion restricts the virus to rapidly proliferating cells [37].

The primary innate antiviral mechanism, type I interferon (IFN), is known to be antiangiogenic, and to promote growth arrest and apoptosis [38]. While many tumours harbour mutations in key IFN genes or epigenetically silence them, the activation of oncogenic pathways or loss of tumour suppressors such as EGFR, Wnt B catenin, or Pten, all have links

to IFN production or responsiveness [39,40]. The net effect is that an estimated 65–70% of cancer cell lines are thought to have defects in their ability to produce, or respond to, type I IFN [41]. Compromised IFN signaling thus underlies the tumour selectivity of OVs and is particularly relevant to Vesicular stomatitis virus (VSV) and Newcastle disease virus (NDV) [41,42]. The safety and specificity of oncolytic VSV is further enhanced through deletion or mutation at position 51 in the matrix protein whose normal function is to block nucleocytoplasmic trafficking of mRNA, thus preventing the translation of IFN and interferon stimulated genes (ISGs) [41,43]. An analogous approach encodes IFNβ in the viral genome, with the added benefit that the cytokine promotes dendritic cell (DC) activation and acts as a signal 3 cytokine for T cell priming [44–46].
