Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes into the artery that leads to tumors

We report that tumor necrosis factor (TNF) Lu induced a strong antitumor im mune reaction when it was produced in arteries leading to tumors by gene tr ansfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the r ight footpad and injected the fusogenic liposomes encapsulating the human T NF-cu gene into the right femoral artery. Under this condition, human TNF-a lpha 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-cu gene wa s delivered into the right femoral artery, with 4 of 11 mice completely cur ed. No regression was observed when the TNF-LU gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was admin istered. Tumor regression was inhibited by the injection of anti-TNF-alpha, anti-CD4, or anti-CDS monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-alpha-treated mice. These results suggest that TNF-alpha expressed locally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction, The si gnificance of this phenomenon for cancer gene therapy was discussed.