Abstract
Oncolytic herpes simplex viruses (oHSVs) are engineered to target and replicate specifically in tumor cells, minimizing damage to normal tissues. This live virus biotherapy entails direct tumor cell killing followed by stimulation of antitumor immunity, leading to abscopal effects in untreated lesions. Currently, there are two clinically approved oHSV biotherapeutics: Imlygic, marketed by Amgen for the treatment of advanced melanoma in the United States and Europe, and Delytact, conditionally approved for recurrent brain tumors in Japan. Lessons learned from initial testing in patients have led to the development of second-generation viruses designed to improve tumor cytotoxicity and/or antitumor immune responses. Preclinical research has also uncovered numerous virus-drug interactions predicted to be synergistic. This has resulted in numerous clinical trials that are currently evaluating these second-generation viruses as single agents or in combination with other antineoplastic therapeutics. As of this review, there are more than 100 clinical trials evaluating their safety and efficacy. Here, we lay out a summary of oHSVs and the rationale behind various virus-drug combinations in clinical trials for patients with different malignancies. We provide a comprehensive review that details the underlying mechanisms of oHSV design and virus-drug interactions that form the basis of their clinical investigation.