Gene therapy with GM-CSF, interleukin-4 and herpes simplex virus thymidine kinase shows strong antitumor effect on lung cancer

Background: Inadequate release of tumor antigens (TA) and a defective antigen presentation by dendritic cells (DC) are the major mechanisms for how tumor cells can escape the host immune surveillance. Materials and Methods: Combined gene therapy of herpes simplex virus thymidine kinase (Tk), GM-CSF and IL-4 via adenoviral vector was tested to solve these problems. After establishing wild-type Lewis lung carcinoma (LLC), vaccinations with LLC transduced with Tk ± GM-CSF ± IL-4 were performed. Results: The LLC-Tk and LLC-Tk-IL-4 vaccination groups failed to suppress the wild-type LLC growth. However, the LLC-Tk-GM-CSF group showed a delayed wild-type tumor growth and LLC-Tk-GM-CSF-IL-4 markedly suppressed tumor growth and increased the survival rate of mice. Immunohistochemistry of the spleen showed a dense infiltration of DCs in the mice treated with LLC-Tk-GM-CSF-IL-4. Conclusion: Combined gene therapy with Tk-GM-CSF-IL-4 was effective in inducing antitumor immunity by enhancing the DC functiuns.