Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress

Viruses have been used for cancer treatment for over a century. From the early clinical studies with various wild-type viruses, to the modern trials with engineered viruses, virotherapy has emerged as a promising therapeutic strategy. The authors discuss the progress and challenges associated with oncolytic virotherapeutic agents, summarizing the data from clinical reports, and the implications of this data for future virotherapy development. Therapeutic oncolytic viruses (virotherapeutics) constitute a novel class of targeted anticancer agents that have unique mechanisms of action compared with other cancer therapeutics. The development of virotherapeutics has evolved from the use of in vitro -passaged strains (first generation), to genetically engineered selectivity-enhanced viruses (second generation) and finally to genetically engineered transgene-expressing 'armed' oncolytic viruses (third generation). Descriptions of cancer remissions following virus infections date back to a century ago. Initial patient treatment publications, written up to 50 years ago, consisted of case reports or case series of treatment with first-generation, non-engineered viruses. Over the past decade, hundreds of patients with cancer have been treated on prospectively designed clinical trials (including phase III), evaluating over 10 different agents, inlcluding engineered second-generation and third-generation viruses. This Review summarizes and interprets the data from clinical reports over the last century, including safety, efficacy and biological end points (viral and immunologic). Systemic safety and efficiacy has been clearly demonstrated with some virotherapeutics. The implications of these data for future virotherapy development are discussed. Key Points Oncolytic viruses can be safely administered into patients via different routes; systemic efficacy has been demonstrated with some virotherapeutics Virus replication can be demonstrated in vivo after local administration, and with some viruses after intravenous administration There is no cross-resistance of oncolytic viruses with standard therapeutics; response to virotherapy is virus species and tumor-specific Virotherapy enhances or synergizes with chemotherapy and radiotherapy Modern technologies have allowed the incorporation of transgenes into oncolytic viruses for therapeutic or monitoring purposes Neutralizing antibodies do not affect efficacy with local and local-regional administration, and the induction of