T-CELL-INDEPENDENT AND NK-CELL-INDEPENDENT INHIBITION OF HEPATIC METASTASES BY SYSTEMIC ADMINISTRATION OF AN IL-12-EXPRESSING RECOMBINANT ADENOVIRUS

IL-12 is a potent immunoregulatory cytokine that has been shown to med iate tumor regression in a variety of tumor models. We describe the co nstruction of AdCMV-IL-12, a recombinant adenovirus that encodes both subunits of IL-12 under transcriptional control of the CMV promoter. T his recombinant virus efficiently infects a wide variety of cell types leading to the production of high levels of biologically active IL-12 , Because the liver is a primary site of infection after i.v.-administ ered adenovirus, we tested the therapeutic efficacy of this virus in a murine hepatic metastasis tumor model, Systemic administration of AdC MV-IL-12 dramatically inhibited the formation of 3-day Renca hepatic m etastases (mean of 16 metastases per liver) compared with the control virus AdCMV-beta gal (mean of 209) or vehicle alone (mean of 272), His tologic analysis indicated that metastatic growth inhibition was accom panied by a dramatic perivascular infiltrate consisting of T Cells, ma crophages, and neutrophils, Therapeutic efficacy was not diminished in animals depleted of CD4(+) or CD8(+) T cells, or in SCID mice, even a fter NK cell ablation, In the latter case, a hepatic perivascular infi ltrate composed of macrophages and neutrophils was observed after AdCM V-IL-12-treatment, while numerous activated Kupffer cells were noted i n the hepatic parenchyma, Analysis of therapy-induced changes in hepat ic gene expression demonstrated increased levels of IP-10 and Mig RNAs , but no increase in iNOS, Fas, or Fast RNA levels was observed. Our d ata suggest a model of metastatic growth inhibition mediated by nonlym phocyte effector cells including macrophages and neutrophils and that may involve anti-angiogenic chemokines.