T cell- 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 mediate tumor regression in a variety of tumor models. We describe the construction of AdCMV-IL-12, a recombinant adenovirus that encodes both subunits of IL-12 under transcriptional control of the CMV promoter. This 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.-administered adenovirus, we tested the therapeutic efficacy of this virus in a murine hepatic metastasis tumor model. Systemic administration of AdCMV-IL-12 dramatically inhibited the formation of 3-day Renca hepatic metastases (mean of 16 metastases per liver) compared with the control virus AdCMV-betagal (mean of 209) or vehicle alone (mean of 272). Histologic analysis indicated that metastatic growth inhibition was accompanied by a dramatic perivascular infiltrate consisting of T cells, macrophages, and neutrophils. Therapeutic efficacy was not diminished in animals depleted of CD4+ or CD8+ T cells, or in SCID mice, even after NK cell ablation. In the latter case, a hepatic perivascular infiltrate composed of macrophages and neutrophils was observed after AdCMV-IL-12-treatment, while numerous activated Kupffer cells were noted in the hepatic parenchyma. Analysis of therapy-induced changes in hepatic gene expression demonstrated increased levels of IP-10 and Mig RNAs, but no increase in iNOS, Fas, or FasL RNA levels was observed. Our data suggest a model of metastatic growth inhibition mediated by nonlymphocyte effector cells including macrophages and neutrophils and that may involve anti-angiogenic chemokines.
Siders
W M
WM
Department of Experimental Transplantation and Immunology, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702, USA.
Wright
P W
PW
Hixon
J A
JA
Alvord
W G
WG
Back
T C
TC
Wiltrout
R H
RH
Fenton
R G
RG
D000230:Adenocarcinoma; D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D007680:Kidney Neoplasms; D007694:Killer Cells, Natural / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000473:pathology; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
D014614:Vaccines, Synthetic; D014765:Viral Vaccines; D018664:Interleukin-12