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There has long been interest in innovating an approach by which tumor cells can be selectively and specifically targeted and destroyed. The discovery of viruses that lyse tumor cells, termed oncolytic viruses (OVs), has led to a revolution in the treatment of cancer. The potential of OVs to improve the therapeutic ratio is derived from their ability to preferentially infect and replicate in cancer cells while avoiding destruction of normal cells surrounding the tumor. Two main mechanisms exist through which these viruses are reported to improve outcomes: direct lysis of tumor cells and indirect augmentation of host anti-tumor immunity. With these factors in mind, viruses are chosen or modified to selectively target tumor cells, decrease pathogenicity to normal cells, decrease the antiviral immune response (to prevent viral clearance), and increase the antitumor immune response. While only one OV has been approved for the treatment of cancer in the United States, and only two other OVs have been approved worldwide, a wide spectrum of OVs are in various stages of preclinical development and in clinical trials. These viruses are being studied as alternatives and adjuncts to more traditional cancer therapies including surgical resection, chemotherapy, radiation, hormonal therapies, targeted therapies, and other immunotherapies. Here, we review the natural characteristics and genetically engineered modifications that enhance the effectiveness of OVs for the treatment of cancer.

Talimogene laherparepvec (TVEC), an oncolytic virus, is an FDA-approved therapy that increases the overall survival of locally advanced and metastatic melanoma patients. Radiation therapy (RT) in combination with immunotherapies improves response rates (compared to either modality alone). Therefore, we hypothesized that combination RT and TVEC results in a synergistic therapeutic effect on melanoma. We treated 8 human melanoma cell lines with radiation (0, 4, or 8 Gy) and/or T-VEC (0, 0.01, 0.1, or 1 MOI) and determined its therapeutic effects using the AlamarBlue cell viability assay. Treatment of UACC257 melanoma cells with combination RT (8 Gy) and TVEC (1 MOI) resulted in a significant decrease in tumor cell viability (a decrease of 44.9%) compared to no treatment, RT alone (33.2%, P=0.0004), or T-VEC alone (24.2%, P=0.0088), with similar findings in other cell lines. We then injected a B16 mouse melanoma cell line, permissive to T-VEC infection, into B6 mice to assess in vivo synergy. Mice were treated when tumors were ~7mm × 7mm. RT resulted in an early 20% decrease in tumor size within 4 days, followed by an increase thereafter. Intra-tumoral TVEC resulted in no clear benefit until 9 days post-treatment, when it showed a slight decrease in size sustained for ~10 days. Combination treatment, however, led to an early response that was sustained until 18 days after the initial treatment. When tumors were assessed 18 days after initial treatment, a 3-fold or more increase in tumor size was lowest in the combination T-VEC + RT group (17%) compared to the control (100%), RT (60%), or TVEC (50%) groups. These data propose that combination T-VEC + RT may be beneficial for cancer patients, and studies establishing the mechanism of synergy are ongoing.