An ongoing phase I II trial NCT is testing this

An ongoing phase I/II trial (NCT02285816) is testing this two virus oncolytic vaccine approach in solid tumours expressing the MAGE-A3 tumour antigen.
Oncolytic Viruses: Repolarizing and Manipulating the Tumour Microenvironment The immune suppressive microenvironment that supports malignant cell growth is a significant hurdle to successful therapeutic intervention. Aside from their direct anti-tumour activity, OVs on their own through the induction of acute localized inflammation, have the capacity to perturb the tumour niche in a way that favours innate and immune attack. This occurs by the production of inflammatory cytokines within the tumour milieu from the infected tumour cell (Breitbach et al., 2007) or as a result of pro-active programming of the virus with immune stimulating cytokines (Li et al., 2011; Patel et al., 2015; Kim et al., 2006). Recently we and others discovered that cytokines like TGF-β which are commonly expressed within the tumour micro-environment (TME) and suppress immune responses also sensitize MaxiPost found within the tumour microenvironment (e.g. cancer associated fibroblasts or CAFs) to OV infection (Ilkow et al., 2015; Han et al., 2015). Similarly FGF-2 expression by CAFs can promote infection of neighboring tumour cells. Thus immune suppressive cytokines produced within the malignancy can paradoxically create a tumour microenvironment that facilitates OV infection and in turn creates a pro-inflammatory setting (Ilkow et al., 2015). Should we consider transiently co-administering particular cytokines with OVs to jumpstart or promote tumour infection? Another common feature of the TME is a disorganized supporting tumour vasculature (Fisher et al., 2016). This is in large part caused by pathological expression of vascular endothelial growth factor (VEGF) which is both immune suppressive and promotes the growth of neovasculature. Recently we discovered that there is cross talk between signaling pathways driven by VEGF and interferon with the transcriptional repressor PRD1/BF1 mediating down-regulation of anti-viral responses in VEGF treated endothelial cells (Arulanandam et al., 2015). These findings suggest that vascular endothelial cells found within the TME may also be targets for OV infection and destruction. Of course whether an OV can infect and destroy tumour vasculature will be dependent upon both this VEGF mediated pro-viral state and also if the endothelial cells express the receptor for a particular OV platform. For viruses like rhabdovirus and poxviruses which have ubiquitously expressed cell receptors attack of tumour vasculature can be readily detected (Breitbach et al., 2013; Kirn et al., 2007; Breitbach et al., 2007, 2011b) in both animal models and cancer patients. Other viruses which have tissue specific receptors will not be able to carry out this same form of anti-tumour attack.
Future Directions Though there has been plenty of investigation into how best to design oncolytic viruses to attack tumours, it is difficult to determine a priori in a heterogeneous patient population which of an OV\'s multiple mechanisms of action is most critical to therapeutic efficacy. There is little doubt that in some animal tumour models (Naik et al., 2012) and likely some patients (Russell et al., 2014), the pure oncolytic activity of an OV may be sufficient to cause therapeutic benefit. In other mouse models where it is possible to rigorously test, oncolysis on its own is insufficient and engagement of the immune system is critical for therapeutic benefit (Pol et al., 2014). It seems reasonable to expect in the human cancer patient population it will be best to attack the tumour with “guns blazing” and use all aspects of the OV armament to advantage. In our view, likely multiple OVs optimally designed to lyse cancer cells, stimulate local inflammatory responses, synergize with emerging immune modulating therapies and delivery therapeutic payloads may be necessary to gain maximum therapeutic benefit from the platform. In pre-clinical models we have shown it is possible to engineer co-operative OVs that can synergistically interact to attack cancers for therapeutic gain (Le Boeuf et al., 2010).