691. Ad-mda7/IL-24 Induces Systemic Anticancer Immunity In Vivo

Abstract

The antitumor activity of human melanoma differentiation associated gene-7 (mda-7)/interleukin 24 (IL24) against human cancer cells has been well established. However, the antitumor activity of mda-7/IL-24 against tumors in immunocompetent mice has not been previously reported. In the present study, we evaluated the antitumor and immune activation of mda-7/IL-24 in murine fibrosarcoma (UV2237m; MCA16) and normal (10T1/2) cells. In vitro, adenovirus-mediated mda-7 gene (Ad-mda7) transfer significantly inhibited growth (P=0.001) and induced apoptosis in tumor cells but not in normal cells. In vivo, administration of Ad-mda7 into subcutaneous tumors resulted in significant inhibition of tumor growth (P<0.05), with a subset of mice showing complete and prolonged tumor regression. Ad-mda7 treated tumor cells had enhanced cell surface expression of major histocompatability complex class I, indicating immune enhancement. We next evaluated the immune potentiation activity of Ad-mda7 in a cancer vaccine model. Vaccination of C3H mice and nude mice with Ad-mda7 treated UV2237m cells resulted in complete tumor inhibition in C3H mice but not in nude mice. These tumor free C3H mice when treated with parental tumor cells experienced no tumor growth, suggesting induction of systemic immunity. Moreover, splenocytes prepared from vaccinated mice demonstrated higher proliferative activity and produced significantly elevated levels of TH1 cytokines compared with those from control mice. An in vitro subset analysis of splenocytes from vaccinated mice demonstrated a significant increase in the CD3+CD8+ but not the CD3+CD4+ cell population (P=0.019). Our results demonstrate that Ad-mda7 treatment of syngeneic tumor cells induces cell death via apoptosis and promotes immune activation, leading to systemic anticancer immunity.