Immuno-gene Therapy of Cancer by Interleukin-21 (IL-21)

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Interleukin-21 (IL-21) is secreted from activated CD4+ T cells, supporting mature T and B lymphocyte proliferation. The cytokine synergizes with IL-15 to promotes expansion and maturation of natural killer (NK) cells. These immunomodulatory functions of IL-21 have been revealed by in vitro studies ; however, the biological implications of IL-21 in vivo have not been fully elucidated. Here, we performed intravascular transfection of IL-21 and/or IL-15 in an experimental murine model of metastatic liver tumors. IL-21 and IL-15 expression plasmids were intravenously injected under high pressure into the tail veins of mice, which were subsequently challenged by an intravenous injection of RLmale1 lymphoma cells. Although the mock-treated and IL-21-transfected mice developed metastatic lymphomas in the liver, IL-15 gene transfection significantly reduced the numbers of metastatic tumor foci. In contrast, when IL-21 and IL-15 genes were co-transfected, complete regression was achieved in 80% of the mice. The cytokine gene therapy was also performed in mice that had been intravenously inoculated with the tumor, cells. Forty percent of mice that received a single injection of a mixture of cytokine genes successfully rejected the pre-established metastatic lymphoma, and showed tumor-free survival for more than 300 days. IL-21 significantly elevated the cytotoxic T lymphocyte (CTL) activity in the spleens of tumor-inoculated mice, while the two cytokines augmented natural killer (NK) killing activity in a synergistic manner. Serum concentrations of interferon-gamma (IFN-gamma), IL-4, and GM-CSF were not significantly affected by the cytokine treatment. These results strongly suggest that the co-administration of genes encoding IL-21 and IL-15 induces powerful antitumor immune responses without causing any severe inflammatory adverse effects, resulting in drastic therapeutic efficacy against metastatic malignancies.