Oncolytic Viruses as an Adjunct to Immune Checkpoint Inhibition

Utilizing viruses in the treatment of cancer, or oncolytic viral therapy (OVT), began in the 1950s with the idea that viruses could invade and destroy cancer cells. Barriers to this approach included a lack of specificity towards cancer cells and intolerable toxicities. However, it was discovered that OVT increases cytokines such as interferon gamma and interleukins within the tumor microenvironment. This "priming" of the tumor microenvironment can lead to an improved innate immunologic response to tumor cells. An "OVT-as-monotherapy" approach has led to modest tumor response rates that have unfortunately not translated well in clinical trials. Currently, only one OVT agent-talimogene laherparevec (TVEC)-has been approved by the FDA for unresectable melanoma with limited visceral metastases. Further advancements in immunotherapy combined with improved viral engineering over the last decade have paved the way for a renewed focus on OVT. For example, various viruses have been modified to infiltrate and upregulate PD-L1 signaling within tumor cells. Upregulation of PD-L1 on tumor cells can increase tumor cell response to immunotherapies that utilize the interaction between PD-L1 on tumor cells and PD-1 on lymphocytes to allow for immune cell destruction of cancer cells. Combining OVT and immunotherapy offers more promise than OVT as monotherapy. Currently, several are actively investigating the combinatorial approach of OVT and immunotherapy in treating non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, melanoma, pancreatic cancer, multiple myeloma, and head and neck squamous cell carcinoma. In this review, we will discuss the history of OVT including its limitations as a monotherapy. We will also discuss the background of combining OVT and immunotherapy including possible benefits and pitfalls of this approach. Lastly, we will review current clinical trials investigating OVT and immunotherapy in multiple cancers.