Systemic IFN-beta gene therapy results in long-term survival in mice with established colorectal liver metastases.
Most patients succumbing to colorectal cancer fail with liver-predominant metastases. To make a clinical impact in this disease, a systemic or whole-liver therapy may be required, whereas most cancer gene therapy approaches are limited in their ability to treat beyond local disease. As a preclinical model for cancer gene therapy, recombinant adenovirus containing the human IFN-beta (hIFN-beta) cDNA was delivered systemically in nude mouse xenograft models of human colorectal cancer liver metastases. The vector targeted hepatocytes that produced high levels of hIFN-beta in the liver, resulting in a profound apoptotic response in the tumors and significant tumor regression. hIFN-beta gene therapy not only resulted in improved survival and long-term cure in a micrometastatic model, but provided similar benefits in a clinically relevant gross disease model. A similar recombinant adenovirus containing the murine IFN-beta (mIFN-beta) cDNA also resulted in a therapeutic response and improved survival in syngeneic mouse models of colorectal cancer liver metastases. Depletion studies demonstrate a contribution of natural killer cells to this therapeutic response. The toxicity of an adenoviral vector expressing murine IFN-beta in a syngeneic model is also presented. These encouraging results warrant further investigation of the use of cancer gene therapy for targeting metastatic disease.
Tada
H
H
Department of Surgery, Division of Surgical Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Maron
D J
DJ
Choi
E A
EA
Barsoum
J
J
Lei
H
H
Xie
Q
Q
Liu
W
W
Ellis
L
L
Moscioni
A D
AD
Tazelaar
J
J
Fawell
S
S
Qin
X
X
Propert
K J
KJ
Davis
A
A
Fraker
D L
DL
Wilson
J M
JM
Spitz
F R
FR
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary* / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D015179:Colorectal Neoplasms / Q000473:pathology*; D003587:Cytomegalovirus / Q000235:genetics; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D005813:Genes, Synthetic; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D016899:Interferon-beta / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use* / Q000633:toxicity; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary* / Q000628:therapy; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000628:therapy; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000502:physiology / Q000627:therapeutic use / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D016899:Interferon-beta