Certainly the jury is still out on the best way

Certainly the jury is still out on the best way to deliver OVs and arguments can be made for either loco-regional or systemic administration. Indeed the flexibility around delivering OVs by different routes, depending on the clinical setting, may be an advantage over more traditional therapeutic modalities. For instance, we could envision administering OVs first by a series of intravenous infusions to ensure maximum distribution of the OV to all metastatic sites followed by multiple intratumoral in situ vaccine boosts. This type of administration regimen has already been piloted with an oncolytic vaccinia virus (NCT01387555, NCT01171651).
Outstanding Questions
Search Strategy and Selection Criteria Data for this Review were identified by searches of PubMed, and references from relevant articles using the search terms “oncolytic viruses”, “immune checkpoint inhibitor”, “immune modulation”, “tumour vasculature”, “cancer vaccines”, “immune adjuvants”, “in situ vaccine” and “tumour microenvironment”. We included reference to one non-peer reviewed opinion article in Biocentury.
Introduction: A Decade-old Cytokine In 2005, Schmitz et al. identified interleukin-33 (IL-33), a 30kDa nuclear cytokine that belongs to the IL-1 family (Schmitz et al., 2005) and that acts as an “alarmin” in response to the cellular damage induced by stress or by infection (Cayrol and Girard, 2014, Moussion et al., 2008). IL-33 is constitutively expressed within the nucleus of endothelial and of epithelial cells, particularly in tissue barrier sites and in fibroblastic reticular kainic acid of the lymph nodes and of the spleen, in which this cytokine contributes to the maintenance of mechanical barriers (Moussion et al., 2008, Martin and Martin, 2016, Schmitz et al., 2005, Peine et al., 2016, Cayrol and Girard, 2014). Furthermore, IL-33, which is released by damaged endothelial and epithelial cells at barrier sites, functions as a damage-associated molecular pattern (DAMP) to trigger activated T-cells, either indirectly through proinflammatory cytokine production by innate immune system cells, or directly in a TCR-independent manner by binding to pattern recognition receptors (PRRs) on T-cells, as recently reviewed (Peine et al., 2016). T-cells can also directly respond to IL-33 via its cognate suppressor of tumorigenicity 2 (ST2) receptor (Smithgall et al., 2008, Peine et al., 2016). IL-33 mainly targets mast cells, basophils, dendritic cells (DCs), macrophages, natural killer (NK) cells, group 2 innate lymphoid cells (ILC2) and T helper 2 (Th2) cells, all of which express ST2 (Jovanovic et al., 2012, Martin and Martin, 2016, Miller, 2011). The ST2 receptor to which the biologically active form of IL-33 binds is a complex consisting of the full-length, transmembrane isoform of ST2 (ST2L), in association with the IL-1 receptor accessory protein (IL-1rap); this receptor complex is expressed at barrier sites and also on certain peripheral blood mononuclear cells including the mast cells, NK cells and Th2 cells (Martin and Martin, 2016, Molofsky et al., 2015a). Conversely, the extracellular IL-33 that is released following cell damage is cleaved in a caspase-dependent and -independent manner, and also undergoes extracellular cysteine oxidation, all of which reduce the efficacy and half-life of IL-33. However, some isoforms of full length extracellular IL-33 and spliced variants of mature IL-33 still possess biological activity (Villarreal and Weiner, 2015, Cayrol and Girard, 2014, Cayrol and Girard, 2009). Moreover, the activity of extracellular IL-33 is controlled by its binding to the soluble form of ST2 (sST2), which serves as a decoy receptor to locally limit ‘off target’ IL-33 activity, thus avoiding inappropriate inflammatory responses (Kakkar and Lee, 2008) Fig. 1. IL-33 was originally found to play a role in innate immunity and in the Th2 response involved in tissue repair following allergic reactions and helminthic infections (Lu et al., 2015). It is now known that IL-33 is also a crucial costimulator in the adaptive immune response, amplifying the responses of antiviral cytotoxic T lymphocytes (CTLs); IL-33 thus acts as an adjuvant (Villarreal et al., 2015b). Furthermore, Schiering et al. have shown that in mice, ST2 is preferentially expressed on colonic Treg cells, thereby allowing IL-33 to promote Treg function by inducing transforming growth factor (TGF)-β1-mediated differentiation of these cells in an inflammatory environment (Schiering et al., 2014).