Gene Therapy for Murine Lung Cancer Using an Adenoviral Vector Expressing lnterleukin-15

Abstract

It has been proven that interleukin-15 (IL-15) has structural and functional features similar to those of interleukin-2 (IL-2). In this study we examined the anti-tumor effect of IL-15 using an adenoviral vector in a mouse model. We constructed an adenoviral vector expressing the IL-15 gene, and introduced it into a mouse Lewis lung carcinoma (LLC) cell line. Then we inoculated pulmonary tissue of a syngeneic mouse strain (C57BL/6 CR) with the IL-15 gene-expressing LLC cells (LLC/IL-15). At the early phase (Day 14), a large number of NK cells accumulated around the IL-15 expressing tumors. At the late phase (Day 28), a much larger number of NK cells had accumulated around the tumors and quite a few NK cells had invaded the IL-15 expressing tumors. The LLC/IL-15-inoculated group survived significantly longer compared to the control groups, i.e., a group inoculated with LacZ gene-expressing LLC cells or a group inoculated with IL-2 gene-expressing LLC cells. After 60 days, the surviving mice of the LLC/IL-15-inoculated group were re-challenged with an additional inoculation of LLC cells alone. Tumor growth was significantly inhibited in the rechallenged LLC/IL-15 group. Induction of cytotoxic T cells was confirmed by interferon-gamma production by splenocytes. We concluded that the IL-15 expressed in the IL-15 expressing tumor cells enhanced the accumulation of NK cells and activated them, leading to suppression of proliferation of the tumor cells.