Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model
Journal
Proceedings of the National Academy of Sciences of the United States of America
Journal Volume
107
Journal Issue
33
Pages
14769-14774
Date Issued
2010
Author(s)
Wu H.-L.
Lin H.-L.
Chen S.-H.
Lee H.-I.
Su P.-Y.
Wu W.-H.
Hwang L.-H.
Chen D.-S.
Abstract
Cytokine and antiangiogenic gene therapies have proved effective in implanted hepatocellular carcinoma (HCC) models in which small tumor burdens were established in small rodents. These models, however, may not reflect human HCCs, which are frequently detected at a stage when tumors are large and multifocal. In addition, HCC in patients is often associated with viral hepatitis. To investigate the effectiveness of a mixture type of gene therapy strategy on large tumor burdens, we used the woodchuck model in which woodchuck hepatitis virus-induced HCCs are large and multifocal, simulating the conditions in humans. Adenoviruses encoding antiangiogenic factors (pigment epithelium-derived factor and endostatin) or cytokines (GM-CSF and IL-12) were delivered via the hepatic artery separately or in combination into woodchuck livers bearing HCCs. Our results showed that the mixture type of strategy, which contained two cytokines and two antiangiogenic factors, had better antitumor effects on large tumors as compared with monotherapy either with antiangiogenic or cytokine genes. The immunotherapy recruited significant levels of CD3 + T cells that infiltrated the tumors, whereas the antiangiogenesis-based therapy significantly reduced tumor vasculature. The mixture type of gene therapy achieved both effects. In addition, it induced high levels of natural killer cells and apoptotic cells and reduced the levels of immunosuppressive effectors in the tumor regions. Hence, antiangiogenic therapy may provide the advantage of reducing immune tolerance in large tumors, making them more vulnerable to the immune reactions. Our study implies that in the future, the combination therapy may prove effective for the treatment of patients with advanced HCC.
SDGs
Other Subjects
adenovirus vector; beta galactosidase; endostatin; granulocyte macrophage colony stimulating factor; interleukin 12; pigment epithelium derived factor; alanine aminotransferase; angiogenesis inhibitor; aspartate aminotransferase; endostatin; eye protein; gamma glutamyltransferase; granulocyte macrophage colony stimulating factor; nerve growth factor; pigment epithelium derived factor; pigment epithelium-derived factor; serine proteinase inhibitor; animal experiment; animal model; animal tissue; antiangiogenic activity; antiangiogenic therapy; apoptosis; article; CD3+ T lymphocyte; controlled study; effector cell; gene therapy; hepatic artery; immunosuppressive treatment; immunotherapy; liver cell carcinoma; lymphocytic infiltration; natural killer cell; nonhuman; priority journal; tumor vascularization; tumor volume; woodchuck; Woodchuck hepatitis virus; animal; blood; gene therapy; genetics; growth, development and aging; hepatitis B; human; liver tumor; metabolism; methodology; multimodality cancer therapy; rodent disease; Sciuridae; treatment outcome; virology; Marmota monax; Rodentia; Woodchuck hepatitis virus; Alanine Transaminase; Angiogenesis Inhibitors; Animals; Aspartate Aminotransferases; Combined Modality Therapy; Endostatins; Eye Proteins; gamma-Glutamyltransferase; Gene Therapy; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatitis B; Hepatitis B Virus, Woodchuck; Humans; Immunotherapy; Liver Neoplasms, Experimental; Marmota; Nerve Growth Factors; Rodent Diseases; Serpins; Treatment Outcome; Tumor Burden
Publisher
National Academy of Sciences
Type
journal article