IL-12 gene therapy is an effective therapeutic strategy for hepatocellular carcinoma in immunosuppressed mice.
Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2(k)), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 x 10(6) MH134 cells (H-2(k)) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-gamma, and IFN-gamma-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2(d)) and tumors, B7-p815 (H-2(d)) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.
Harada
Noboru
N
Department of, Surgery and Science, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. nharada@surg2.med.kyushu-u.ac.jp
Shimada
Mitsuo
M
Okano
Shinji
S
Suehiro
Taketoshi
T
Soejima
Yuji
Y
Tomita
Yukihiro
Y
Maehara
Yoshihiko
Y
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D004306:Dose-Response Relationship, Immunologic; D018274:Electroporation; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006084:Graft Rejection / Q000517:prevention & control; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D016038:Skin Transplantation / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016559:Tacrolimus / Q000008:administration & dosage
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D018664:Interleukin-12; D016559:Tacrolimus