Interleukin-12 gene transfer results in CD8-dependent regression of murineCT26 liver tumors

Background: Interleukin, (IL)-12 has potent antitumor effects in animal mod els. 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 murin e adenocarcinoma, into the livers of BALB/c mice, followed by three transfe ctions with either murine IL-12, murine granulocyte-macrophage colony-stimu lating factor, or luciferase cDNA using particle-mediated gene transfer. To assess the mechanism of this effect, immunohistochemical staining and depl etion experiments with anti-CD4 or -CD8 antibodies were performed. Results: Progressive growth of primary tumors and carcinomatosis were prese nt by day 16 after transfection with luciferase or murine granulocyte-macro phage colony-stimulating factor. At 50 days, complete regression of tumor w as evident in seven of eight IL-12-treated mice (P < .001). In IL-12-transf ected Livers, immunohistochemical staining revealed an increase in CD8(+) T cells. Selective depletion of CD4(+) or CD8(+) T cells was performed befor e and during transfection with murine IL-12. Al 50 days, 75% of control mic e 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 resu lts in complete regression of established CT26 liver tumors in 88% of mice; this effect is dependent on CD8(+) T cells.