Eradication of intraperitoneal and distant tumor by adenovirus-mediated interferon-beta gene therapy is attributable to induction of systemic immunity

Malignant mesothelioma remains an incurable disease for which immune-modula tory therapies, such as exogenous cytokines, have shown some promise. One s uch cytokine, IFN-beta, has potent antiproliferative and immunostimulatory activity in vitro, but its in vivo use has been limited by toxicity. We thu s conducted studies evaluating intracavitary delivery of a replication-defi cient adenoviral (Ad) vector encoding for the marine IFN-beta gene (Ad.muIF N-beta) in mouse models of malignant mesothelioma. In contrast to multiple injections of recombinant protein, a single i.p. injection of Ad.muIFN-beta into animals with established tumors elicited remarkable antitumor activit y leading to long-term survival in > 90% of animals bearing either AB12 or AC29 i.p. mesotheliomas. A control adenovirus vector had minimal antitumor effect in vivo. Significant therapeutic effects were also seen in animals t reated with large tumor burdens. Importantly, treatment of i.p. tumor also led to reduction of growth in tumors established at a distant site (flank). A number of experiments suggested that these effects were attributable to an acquired CD8(+) T-cell-mediated response including: (a) the induction of long-lasting antitumor immunity; (b) loss of efficacy of Ad.muIFN-beta in tumor-bearing, immune-deficient (SCID, SCID/beige) mice; (c) detection of h igh levels of specific antitumor cytolytic activity from unstimulated splen ocytes harvested from Ad.muIFN-beta -treatcd animals that was abolished by CD8(+) T-cell depletion; and (d) abrogation of antitumor effects of Ad.muIF N-beta in tumor-bearing CD8(+) T-cell-depleted animals. These data show tha t intracavitary IFN-beta gene therapy using an adenoviral vector provides s trong CD8(+) T-cell-mediated antitumor effects in marine models of mesothel ioma and suggest that this may be a promising strategy for the treatment of localized tumors such as mesothelioma or ovarian cancer in humans.