Combining antiangiogenic therapy with immunotherapy exerts better therapeutical effects on large tumors in a woodchuck hepatoma model.
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.
Huang
Kai-Wen
KW
Hepatitis Research Center, Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
Wu
Hui-Lin
HL
Lin
Hsiu-Lin
HL
Liang
Po-Chin
PC
Chen
Pei-Jer
PJ
Chen
Shih-Hui
SH
Lee
Hsin-I
HI
Su
Pei-Yi
PY
Wu
Wen-Hsuan
WH
Lee
Po-Huang
PH
Hwang
Lih-Hwa
LH
Chen
Ding-Shinn
DS
D000410:Alanine Transaminase / Q000097:blood; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003131:Combined Modality Therapy; D043169:Endostatins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006509:Hepatitis B / Q000150:complications / Q000821:virology; D017919:Hepatitis B Virus, Woodchuck / Q000254:growth & development; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000209:etiology / Q000628:therapy*; D008392:Marmota; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D012376:Rodent Diseases / Q000097:blood / Q000209:etiology / Q000628:therapy*; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden; D005723:gamma-Glutamyltransferase / Q000097:blood; D000099174:Pigment Epithelium-Derived Factor
D000410:Alanine Transaminase; D020533:Angiogenesis Inhibitors; D001219:Aspartate Aminotransferases; D043169:Endostatins; D005136:Eye Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009414:Nerve Growth Factors; D015843:Serpins; D005723:gamma-Glutamyltransferase; D000099174:Pigment Epithelium-Derived Factor