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Interleukin-15 is a pleiotropic cytokine that has potential for cancer immunegene therapy. We previously reported the construction and characterization of IL-15 overexpression vectors pHi2-IL15-CMV-tat (L1) and pHi2-spIL15-CMV-tat (L3), as well as carcinoembryonic antigen promoter-amplified IL-15 expression plasmid vectors pHi2-IL15-CEA-tat (L2) and pHi2-spIL15-CEA-tat (L4). In the current study, we evaluated the expression and therapeutic efficacy of these vectors using a mouse colon carcinoma model. Plasmid vectors were transfected into SW480 and MCF-7 cells, and IL-15 overexpression was confirmed. IL-15 expressed by transfected tumor cells stimulated spleen cell proliferation in vitro. Intraperitoneal injection of plasmid pHi2-spIL15-CMV-tat (L3) into mice resulted in transgene expression by peritoneal mesothelial cells, inhibited CT-26 tumor growth and prolonged the survival of tumor-bearing mice. In addition, the in vivo transfection of plasmid pHi2-spIL15-CMV-tat (L3) via electroporation slowed the tumor formation of subcutaneously inoculated CT-26 cells. These data suggest that IL-15 overexpression achieves therapeutic effects in a mouse cancer model and that these gene transfer approaches should be further evaluated for use in the treatment of human cancers.

Interleukin-15 (IL-15) is a pleiotropic cytokine that plays a key role in the regulation of both innate and adaptive immune responses. It promotes the survival, proliferation, activation and maintenance of natural killer and CD8+ T cells. It also stimulates the function of neutrophils, macrophages and dendritic cells, and could therefore be a potential cytokine for cancer immune therapy. The therapeutic effects of cytokines are related to their expression levels. In this study, we investigated an amplified IL-15 expression plasmid vector, pHi2-spIL15-CMV-tat, and a carcinoembryonic antigen (CEA)-positive tumor-specific amplified IL-15 expression plasmid vector, pHi2-spIL15-CEA-tat. In pHi2-spIL15-CMV-tat, IL-15 expression was driven by HIV2 LTR, which was transactivated by CMV promoter-controlled expression of HIV tat. In addition, the native IL-15 signal peptide was replaced by the IL-2 signal peptide to enhance its secretion. A significant amount of IL-15 expression was achieved when transfected into tumor cells in vitro. In order to target IL-15 expression in CEA-positive cells, the CEA promoter positively-controlled IL-15 expression plasmid vector pHi2-spIL15-CEA-tat was constructed by replacing the CMV with the CEA promoter. Efficient and targeted IL-15 expression was achieved in CEA-positive tumor cells by pHi2-spIL15-CEA-tat.