The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-gamma-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti-angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1 alpha, HIF-2 alpha and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti-angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature.

In the past several years, cancer treatments using FDA approved immune checkpoint inhibitors have become more popular than common chemotherapeutic agents. However, the costs, risks, and benefits associated with these treatments are still being assessed. Currently, new therapies are being tested that utilize oncolytic viruses to treat solid tumor and metastatic cancers. Reovirus is a non-enveloped virus with a double capsid structure and a genome consisting of 10 segments of double-stranded RNA encoding eleven proteins, which has been shown to have effective oncolytic activity. There are various different strains of reoviruses that can produce cytopathic effects in mammalian host cells. Moreover, several studies have shown that reovirus can be administered in multiple ways and that administration may depend on the cancer type. This investigation examined the type 3 dearing strain of reovirus and whether different types of tumors would benefit from having a specific administration appropriate to their type such as intratumoral injections for solid tumors and intravenous administration for blood/metastatic cancers. Various clinical trials were assessed in which reovirus was administered intratumorally, intravenously at a maximum dose of 3x1010 TCID50, and in combinations with other cancer therapeutics. Reovirus was shown to be safe and well-tolerated across a variety of administrations and cancer morphologies. Moreover, along with its cytopathic effects, reovirus was shown to have potent immune system stimulating effects. Overall, intratumoral administration was preferred effective for solid tumor cancers while intravenous administration was preferred for blood and metastatic cancers.