Abstract
Over the past decade, oncolytic viruses (OVs) have been developed as a promising treatment alone or in combination in immuno-oncology but have faced challenges in late-stage clinical trials. Our retrospective reanalysis of vaccinia oncolytic virus (VOV) clinical trials indicates that lower doses-rather than the maximum tolerated dose (MTD)-are associated with better tumor response rates. Patients who responded well to lower doses generally had prolonged survival rates in the early phase clinical trial. The association between poor outcomes and an increase in OV-induced neutrophils (OV-N) but not baseline neutrophil counts suggests the need for a comprehensive characterization of OV-N. Although this reanalysis is limited by patient heterogeneity-including differences in cancer type and stage, treatment schedules, and administration routes-it remains informative given the complexities of translational studies in the tumor-bearing mouse models of vaccinia oncolytic viruses. Notably, while OV-N increases with higher viral doses, the immune state shaped by tumor progression likely amplifies this tendency. These findings highlight the importance of OV-N immune modulation as well as dose optimization for the successful clinical development of VOV.