Interleukin-12 Gene Transfer Results in CD8-Dependent Regression of Murine CT26 Liver Tumors

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Abstract
Background: Interleukin (IL)-12 has potent antitumor effects in animal models. We hypothesized that direct transfer of the IL-12 gene to established tumors would result in tumor regression without significant toxicity. Methods: Liver tumors were established by direct injection of CT26, a murine adenocarcinoma, into the livers of BALB/c mice, followed by three transfections with either murine IL-12, murine granulocyte-macrophage colony-stimulating factor, or luciferase cDNA using particle-mediated gene transfer. To assess the mechanism of this effect, immunohistochemical staining and depletion experiments with anti-CD4 or -CD8 antibodies were performed. Results: Progressive growth of primary tumors and carcinomatosis were present by day 16 after transfection with luciferase or murine granulocyte-macrophage colony-stimulating factor. At 50 days, complete regression of tumor was evident in seven of eight IL-12-treated mice (P < .001). In IL-12-transfected livers, immunohistochemical staining revealed an increase in CD8+ T cells. Selective depletion of CD4+ or CD8+ T cells was performed before and during transfection with murine IL-12. At 50 days, 75% of control mice were tumor-free. Only 46% of CD4+ cell-depleted mice (P = .143) and 7% of CD8+ cell-depleted mice (P < .001) were tumor-free. Conclusions: IL-12 gene transfer using particle-mediated gene transfer results in complete regression of established CT26 liver tumors in 88% of mice; this effect is dependent on CD8+ T cells.