The Efficacy of Coxsackievirus A21 in Combination with Radiotherapy for the Treatment of Colorectal Cancer

Colorectal cancer (CRC) is a common malignancy which is gradually increasing in incidence. Survival is closely associated with stage of disease, with metastatic colorectal cancer having a five-year survival of less than 10%. Up to 40% of patients with CRC present at a late stage, already with metastatic burden, and up to 40% of patients with CRC who are treated with curative intent will go on to develop either local recurrence or metachronous metastases. There is therefore substantial scope with which to develop novel treatments that can improve outcome and decrease recurrence risk within this common disease. Oncolytic viruses (OV) are a novel form of cancer treatment with only a few approved treatments thus far. They are viruses with low pathogenicity which preferentially infect and kill cancerous cells due to their altered molecular architecture. In addition to direct lytic killing, OVs have the capacity to induce an anti-tumour immune response, which not only provides a secondary mode of tumour cell death but could potentially provide prolonged protection against tumour recurrence. The use of OVs in the treatment of CRC is in the early stage of research. Within this study we aimed to investigate the potential use of one such OV, Coxsackievirus A21 (CVA21) against CRC. This is the first time this particular OV has been studied within the context of CRC. Here, we have demonstrated that CVA21 exhibits direct cytotoxic effects on CRC cell lines, the extent of which correlates positively with the level of expression of CVA21 entry receptors. In addition to direct mediated cytotoxicity, we have also demonstrated that CVA21 infection activates NK cells and thereby results in immune-mediated death of CRC in vitro. Importantly, within this study we have shown that the concurrent use of radiotherapy results in enhancement of CVA21 cytotoxicity against CRC, both via direct and indirect cytotoxic pathways. This is highlighted by the demonstration of de novo viral replication within resistant cell lines, increased reduction in cell viability and enhanced NK cell-mediated death seen in all cell lines following dual treatment. Crucially, this enhanced response is demonstrated in CRC cell lines resistant to either treatment in isolation. In summary, we have demonstrated that CVA21 not only has significant potential as a treatment for CRC, but as an adjunct alongside standard therapies could further enhance their treatment of CRC.