An oncolytic vaccinia virus armed with gm-csf and il-24 double genes for cancer targeted therapy

Abstract

Purpose: Targeted oncolytic vaccinia virus is an attractive candidate for cancer therapy due to its replication causing lysis of infected tumor cells as well as a delivery vector to overexpress therapeutic transgenes. This study constructed a novel oncolytic vaccinia virus carrying granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-24 (IL-24) double genes to improve efficacy for cancer therapy. Methods: Vaccinia virus co-expressing GM-CSF and IL-24 based on Chinese Guang9 strain (VG9-GMCSF-IL24) was constructed with disruption of the viral thymidine kinase (TK) gene. The cytotoxicity of VG9-GMCSF-IL24 in various cell lines was assessed by MTT. The synergistic antitumor effect of VG9-GMCSF-IL24 in vivo was assessed on multiple tumor models. Results: In vitro cytotoxicity assay showed that VG9-GMCSF-IL24 exerted a strongly cytotoxic effect on cancer cells, but with no significant cytotoxicity to normal cells. Significant tumor growth inhibition and prolonged survival were observed in different tumor models treated with VG9-GMCSF-IL24. Additionally, systemic and specific antitu-moral immunity was investigated in vivo, and enhanced antitumor immunity was observed in VG9-GMCSF-IL24-treated mice. Conclusion: Our results indicated that VG9-mediated GM-CSF and IL-24 co-expression performed cooperative and overlapping antitumor effect. As a novel and effective therapeutic strategy for cancer, the combination of oncolysis and immunotherapy with vaccinia virus carrying one or more immunostimulatory genes may have a satisfactory clinical application prospect.