Optimization and preclinical design of genetically engineered viruses for human oncolytic therapy

Introduction: Oncolytic viruses (OVs) occupy a strategic niche in the dynamic era of biological and gene therapy of human cancers. However, the use of OVs is the subject of close scrutiny due to impediments such as the insufficiency of patient generalizations posed by heterogeneous tumor responses to treatment, inherent or potentially lethal viral pathogenicities, unanticipated host- or immune-related adverse effects, and the emergence of virus-resistant cancer cells. These challenges can be overcome by the design and development of more definitive (optimized, targeted, and individualized) cancer virotherapeutics. Areas covered: The translation of current knowledge and recent innovations into rational treatment prospects hinges on an iterative loop of variables pertaining to genetically engineered viral oncolytic efficacy and safety profiles, mechanism-of-action data, potencies of synergistic oncolytic viral combinations with conventional tumor, immuno-, chemo-, and radiation treatment modalities, optimization of the probabilities of treatment successes in heterogeneous (virus-sensitive and -resistant) tumor cell populations by mathematical modeling, and lessons learned from preclinical studies and human clinical trials. Expert opinion: In recent years, it has become increasingly clear that proof-of-principle is critical for the preclinical optimization of oncolytic viruses to target heterogeneous forms of cancer and to prioritize current concerns related to the efficacy and safety of oncolytic virotherapy.