Administration route-dependent induction of antitumor immunity by interferon-alpha gene transfer

Type I interferon (IFN) protein is a cytokine with pleiotropic biological functions that include induction of apoptosis, inhibition of angiogenesis, and immunomodulation. We have demonstrated that intratumoral injection of an IFN-alpha-expressing adenovirus effectively induces cell death of cancer cells and elicits a systemic tumor-specific immunity in several animal models. On the other hand, reports demonstrated that an elevation of IFN in the serum following an intramuscular delivery of a vector is able to activate antitumor immunity. In this study, we compared the intratumoral and systemic routes of IFN gene transfer with regard to the effect and safety of the treatment. Intratumoral injection of an IFN-alpha adenovirus effectively activated tumor-responsive lymphocytes and caused tumor suppression not only in the gene-transduced tumors but also in distant tumors, which was more effective than the intravenous administration of the same vector. The expression of co-stimulatory molecules on CD11c(+) cells isolated from regional lymph nodes was enhanced by IFN gene transfer into the tumors. Systemic toxicity such as an elevation of hepatic enzymes was much lower in mice treated by intratumoral gene transfer than in those treated by systemic gene transfer. Our data suggest that the intratumoral route of the IFN vector is superior to intravenous administration, due to the effective induction of antitumor immunity and the lower toxicity.