Review: Oncolytic virotherapy, updates and future directions

Abstract

Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma. Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects. Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral-induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition.

Keywords: cytotoxicity; immunotherapy; oncolytic virus.

Figure 1. Mechanisms of action of oncolytic viruses

DAF – Decay Accelerating Factor, GM-CSF – Granulocyte Macrophage-Colony Stimulating Factor, HSV – Herpes Simplex Virus, hTERT – Human Telomerase, ICAM-1 – Intercellular Adhesion Molecule-1, ICP – Infectious Cell Protein, INF-β – Interferon beta, NDV – Newcastle Disease Virus, VSV – Vesicular Stomatitis Virus.