Tumor Necrosis Factor α-mediated Tumor Regression by the in Vivo Transfer of Genes into the Artery That Leads to Tumors¹

We report that tumor necrosis factor (TNF) α induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-α gene into the right femoral artery. Under this condition, human TNF-α was detected only in the artery leading to the tumor and in the tumor. There was a significant regression in tumor growth when the TNF-α gene was delivered into the right femoral artery, with 4 of 11 mice completely cured. No regression was observed when the TNF-α gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was administered. Tumor regression was inhibited by the injection of anti-TNF-α, anti-CD4, or anti-CD8 monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-α-treated mice. These results suggest that TNF-α expressed locally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction. The significance of this phenomenon for cancer gene therapy was discussed.