Wm. Siders et al., T-CELL-INDEPENDENT AND NK-CELL-INDEPENDENT INHIBITION OF HEPATIC METASTASES BY SYSTEMIC ADMINISTRATION OF AN IL-12-EXPRESSING RECOMBINANT ADENOVIRUS, The Journal of immunology, 160(11), 1998, pp. 5465-5474
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.