Gene transfer of IFN-gamma into established brain tumors represses growth by antiangiogenesis

The experiments in this paper were designed to examine the therapeutic effe cts of adenoviral-mediated gene transfer of IFN-gamma into a mouse model of an established metastatic brain tumor, Temperature-sensitive replication d efective adenovirus was generated for gene transfer of IFN-gamma (AdIFN) an d beta-galactosidase (AdBGAL) cDNAs in vivo. In this model, treatment with AdIFN elicits prolonged survival times and brain tumor rejection. Evidence against an immune-mediated response accounting for this result include: 1) absence of a memory immune response upon challenge, 2) lack of antitumor ef fects at sites distal to inoculation of AdIFN, and 3) preservation of the t herapeutic effects of AdIFN in acid and beige mice and in inducible NO synt hase (MOS) knockouts. High concentrations of IFN-gamma do not inhibit tumor growth in vitro making it unlikely that the antitumor effect of this treat ment acts directly on the growth of the tumor cells, However, gene transfer of IFN-gamma inhibits neovascularization of the tumor in a 3LL-Matrigel as say in vivo, and AdIFN induces apoptosis of endothelial cells in vivo, supp orting the idea that AdIFN represses tumor growth by inhibiting angiogenesi s. The substantial non-immune-mediated therapeutic benefits of AdIFN in ani mals paves the way for devising novel strategies for treating human brain t umors.