Oncolytic Viruses and Immune Checkpoint Inhibitors: The "Hot" New Power Couple

Simple Summary Oncolytic viruses (OV) are engineered viruses designed to replicate selectively within tumour cells. They hold great promise as novel cancer therapeutics, but their performance clinically has, to date, failed to match expectations. One area of increasing interest in OV is the ability of these agents to induce lytic ("bursting") cell death of tumour cells through replication. This lytic form of cell death is highly immunogenic, and therefore has the capacity to immunologically "heat up" otherwise "cold" tumours. Immune checkpoint inhibitors have revolutionized cancer immunotherapies, but frustratingly are only effective in a subset of patients with high levels of tumour infiltrating lymphocytes. There is increasing excitement that the combinations of OV with immune checkpoint inhibitors, or even immune checkpoint inhibitors encoded by OV, may prove synergistic, and have the potential to treat recalcitrant, immunologically cold tumours. Here, we review the evidence to date that such combination strategies may prove efficacious.Abstract Immune checkpoint inhibitors (ICIs) have revolutionized cancer care and shown remarkable efficacy clinically. This efficacy is, however, limited to subsets of patients with significant infiltration of lymphocytes into the tumour microenvironment. To extend their efficacy to patients who fail to respond or achieve durable responses, it is now becoming evident that complex combinations of immunomodulatory agents may be required to extend efficacy to patients with immunologically "cold" tumours. Oncolytic viruses (OVs) have the capacity to selectively replicate within and kill tumour cells, resulting in the induction of immunogenic cell death and the augmentation of anti-tumour immunity, and have emerged as a promising modality for combination therapy to overcome the limitations seen with ICIs. Pre-clinical and clinical data have demonstrated that OVs can increase immune cell infiltration into the tumour and induce anti-tumour immunity, thus changing a "cold" tumour microenvironment that is commonly associated with poor response to ICIs, to a "hot" microenvironment which can render patients more susceptible to ICIs. Here, we review the major viral vector platforms used in OV clinical trials, their success when used as a monotherapy and when combined with adjuvant ICIs, as well as pre-clinical studies looking at the effectiveness of encoding OVs to deliver ICIs locally to the tumour microenvironment through transgene expression.