Survival benefit of KRN7000 immune therapy in combination with TNP470 in hamster liver metastasis model of pancreatic cancer.
Pancreatic cancer is a solid malignancy with the poor prognosis largely due to frequent and lethal liver metastases. The combination of immunotherapy and anti-angiogenesis therapy might be a hopeful strategy for the treatment of distant metastases. The benefits of the combination therapy by an immune stimulator alpha-galactosylceramide (KRN7000) and an angiogenesis inhibitor AGM-1470 (TNP470) were evaluated on the hamster highly aggressive liver metastasis model using the syngeneic pancreatic cancer cell line HPD-NR. KRN7000 immediately activated hepatic mono-nuclear cells to produce IFN-gamma in vitro. Intraportal injection of KRN7000 exhibited a dense accumulation of CD4-CD8- natural killer T cells, around the liver metastases in vivo. KRN7000 treatment significantly inhibited the growth of liver metastases, and importantly, significant survival prolongation was confirmed when TNP470 treatment was added to it. Furthermore, cytotoxic T lymphocytes were induced at the sites of a few residual metastases in the liver of a long-term survivor. Thus, the combination of KRN7000 and TNP470 showed a high effectiveness for the treatment of liver metastases of pancreatic cancer.
Matsumoto
Gaku
G
Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo 113-8677, Japan.
Nagai
Shigenori
S
Muta
Mariko
M
Tsuruta
Koji
K
Okamoto
Atsutake
A
Toi
Masakazu
M
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015704:CD4 Antigens / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D002455:Cell Division; D006224:Cricetinae; D003510:Cyclohexanes; D004195:Disease Models, Animal; D005699:Galactosylceramides / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary; D008297:Male; D008647:Mesocricetus; D009362:Neoplasm Metastasis; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010190:Pancreatic Neoplasms / Q000150:complications / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D015704:CD4 Antigens; D016827:CD8 Antigens; D003510:Cyclohexanes; D005699:Galactosylceramides; D012717:Sesquiterpenes; D007371:Interferon-gamma; C103873:KRN 7000; D000077609:O-(Chloroacetylcarbamoyl)fumagillol