Oncolytic Herpes Virus G47∆ Potentiates ADCC-Inducing Molecular Targeted Therapy via Coordinated Activation of Innate and Adaptive Immune Responses

Antibody-dependent cellular cytotoxicity (ADCC) is a key player in the antitumor immunity elicited through molecular targeted therapy of oncogenic receptors using monoclonal antibodies (mAbs). Oncolytic viruses represent an alternative therapeutic means that selectively replicate in and destroy tumor cells, as well as induce specific antitumor immune responses. This study investigates whether oncolytic virus therapy using G47∆, a third-generation oncolytic herpes virus with enhanced induction of antitumor immunity, can augment the efficacy of molecular targeted therapy with ADCC, using the anti-epidermal growth factor receptor (EGFR) mAb cetuximab. Due to the species specificity of cetuximab, we developed a human EGFR-expressing immunocompetent murine tumor model specific to the ADCC activity of cetuximab. Intratumoral G47∆ administration combined with systemic cetuximab treatment was significantly more effective in suppressing tumor growth than G47∆ monotherapy. This phenomenon was dependent upon the activation of both innate and adaptive immune cells, as antitumor responses were abrogated upon natural killer (NK) cell and CD8+ T cell depletions. Further studies investigating the draining lymph node dendritic cells (DCs) indicate that the destruction of cetuximab-coated tumor cells by G47Δ promotes uptake of tumor cells by DCs, enhances the priming of immune responses, and subsequently stimulates tumor-specific CD8+ T cells. These results suggest that the combination of G47Δ therapy and molecular targeted therapies with ADCC activity may represent a useful therapeutic strategy for enhancing antitumor immune responses, even after the emergence of acquired resistance.