348. IL-21 and IL-15 Gene Therapy Induces Powerful Antitumor Effect Against Head and Neck Squamous Cell Carcinoma
Authors: Hiroshi Nakano, Tsunao Kishida, Hidetsugu Asada, Takashi Shinomiya, Jiro Imanishi, Yasuo Hisa, Osamu Mazda
Journal: Molecular Therapy (2004)

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Interleukin (IL)-21 is a member of the 4-helix-bundle cytokine family capable of supporting proliferation of mature T and B lymphocytes. The cytokine also facilitates expansion and maturation of natural killer (NK) cells in synergy with IL-15. We previously reported that intravascular transfection of IL-21 and IL-15 genes augmented antitumor immunity, resulting in a marked therapeutic outcome in a hepatic metastasis model of lymphoma in mice (Kishida et al. Molecular Therapy, 8:552, 2003). It remains to be elucidated, however, whether the combinatory cytokine gene therapy could also inhibit a pre-established solid tumor in vivo. In the present study, we investigated the efficacy of intravascular delivery of IL-21 and IL-15 genes in suppressing head and neck squamous cell carcinoma (HNSCC) implant in mice.

SCCVII, a murine HNSCC cell line, was subcutaneously inoculated into the flank of syngenic C3H/He mice to develop palpable subcutaneous tumors. A plasmid vector encoding murine IL-21 was intravenously injected into the tumor-bearing mice via their tail vein, alone or in combination with an IL-15 expression vector construct. The genetic transfer of either IL-21 or IL-15 elicited a significant, but moderate, antitumor effect compared with the treatments with an empty plasmid. In contrast, a remarkable antitumor effect was obtained by repetitive transfection with both the IL-21 and IL-15 genes, leading to a significant prolongation of the survival periods of the animals (P<.05, IL-21+IL-15 vs IL-21 alone; P<0.05, IL-21+IL-15 vs IL-15 alone; P<0.005, IL-21+IL-15 vs control), although a single treatment with both of the cytokine genes failed to show such therapeutic results. Importantly, any detectable toxic effect such as body weight loss and capillary leaking was not revealed in the mice that had received these cytokine genes. IL-21 significantly elevated cytotoxic T lymphocyte (CTL) killing activity against the SCCVII in the spleen of the tumor-bearing mice (P<0.005, IL-21+IL-15 vs control; P<0.05, IL-21 alone vs control), while IL-21 and IL-15 augmented NK cytotoxicity (P<0.0005, IL-21+IL-15 vs control; P<0.001, IL-21+IL-15 vs IL-21 alone; P<0.005, IL-21+IL-15 vs IL-15 alone). The co-transfection with IL-21 and IL-15 genes slightly, but significantly, elevated the production of interferon (IFN)-γ in the liver compared with the delivery of either IL-21, IL-15, or control plasmids, whereas IFN-γ concentration in the sera was not significantly affected. Furthermore, IL-21 gene transfection induced production of immunoglobulin specific for SCCVII tumor antigen, as demonstrated by indirect cellular ELISA and flowcytometric analyses of the sera from the genetically modified tumor bearers (P<0.05, IL-21+IL-15 vs control; P<0.005, IL-21 alone vs control). Taken together, the present study strongly suggest that the IL-21 and IL-15 genes synergistically elicited powerful cellular and humoral antitumor immune responses, which effectively suppressed HNSCC-derived pre-established tumor without any detectable adverse effect in vivo.