Abstract
Among various immunotherapeutic approaches, interleukin-12 (IL-12) is particularly appealing because of its superior antitumor effects, which have been demonstrated in preclinical as well as clinical studies. However, IL-12 therapy was often accompanied by severe side effects due mainly to the supranormal induction of interferon-γ. To optimize the therapeutic efficacy and lower the side effects of IL-12, we have investigated the antitumor activity of combined IL-12 and granulocyte–macrophage colony-stimulating factor (GM-CSF) gene therapy in a highly malignant and poorly immunogenic murine hepatocellular carcinoma model. Using a versatile hydrodynamics-based DNA delivery method, we showed that the combined gene delivery of IL-12 and GM-CSF induced very strong antitumor cellular immunity and achieved significant therapeutic efficacy, whereas each cytokine gene alone yielded appreciable but less effects. We also observed that the combined therapy induced lower levels of interferon-γ than did IL-12 alone. These results suggest that combined IL-12 and GM-CSF therapy can render a stronger antitumor effect as well as lowering potential side effects. Cancer Gene Therapy (2001) 8, 751–758
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References
Brunda MJ, et al . Antitumor activity of interleukin 12 in preclinical models Cancer Chemother Pharmacol 1996 38: S16–S21
Rodolfo M, Colombo MP . Interleukin-12 as an adjuvant for cancer immunotherapy Methods 1999 19: 114–120
Trinchieri G, Scott P . Interleukin-12: basic principles and clinical applications Curr Top Microbiol Immunol 1999 238: 57–78
Hendrzak JA, Brunda MJ . Antitumor and antimetastatic activity of interleukin-12 Curr Top Microbiol Immunol 1996 213: 65–83
Golab J, Zagozdzon R . Antitumor effects of interleukin-12 in pre-clinical and early clinical studies (Review) Int J Mol Med 1999 3: 537–544
Tsung K, Meko JB, Peplinski GR, Tsung YL, Norton JA . IL-12 induces T helper 1–directed antitumor response J Immunol 1997 158: 3359–3365
Puddu P, et al . IL-12 induces IFN-gamma expression and secretion in mouse peritoneal macrophages J Immunol 1997 159: 3490–3497
Chan SH, Kobayashi M, Santoli D, Perussia B, Trinchieri G . Mechanisms of IFN-gamma induction by natural killer cell stimulatory factor (NKSF/IL-12). Role of transcription and mRNA stability in the synergistic interaction between NKSF and IL-2 J Immunol 1992 148: 92–98
Chehimi J, et al . Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus–infected patients J Exp Med 1992 175: 789–796
Brunda MJ, et al . Antitumor and antimetastatic activity of interleukin 12 against murine tumors J Exp Med 1993 178: 1223–1230
Cohen J . IL-12 deaths: explanation and a puzzle Science 1995 270: 908
Car BD, et al . Role of interferon-gamma in interleukin 12–induced pathology in mice Am J Pathol 1995 147: 1693–1707
Car BD, Eng VM, Lipman JM, Anderson TD . The toxicology of interleukin-12: a review Toxicol Pathol 1999 27: 58–63
Boyer MW, et al . Cytokine upregulation of the antigen-presenting function of acute myeloid leukemia cells Leukemia 2000 14: 412–418
Jager E, et al . Granulocyte–macrophage colony-stimulating factor enhances immune responses to melanoma-associated peptides in vivo Int J Cancer 1996 67: 54–62
Wang J, et al . Transgenic expression of granulocyte–macrophage colony-stimulating factor induces the differentiation and activation of a novel dendritic cell population in the lung Blood 2000 95: 2337–2345
Williams MA, Kelsey SM, Newland AC . GM-CSF and stimulation of monocyte/macrophage function in vivo relevance and in vitro observations Eur J Cancer 1999 35: S18–S22
Kayaga J, et al . Anti-tumour activity against B16-F10 melanoma with a GM-CSF secreting allogeneic tumour cell vaccine Gene Ther 1999 6: 1475–1481
Mellstedt H, Fagerberg J, Osterborg A . Local low-dose of soluble GM-CSF significantly augments an immune response against tumour antigens in man Eur J Cancer 1999 35: S29–S32
Roth MD, et al . Granulocyte–macrophage colony-stimulating factor and interleukin 4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients Cancer Res 2000 60: 1934–1941
Tatsumi T, et al . B7-1 (CD80) gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma Hepatology 1999 30: 422–429
Drozdzik M, et al . Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma J Hepatol 2000 32: 279–286
Sun Y, Qian C, Peng D, Prieto J . Gene transfer to liver cancer cells of B7-1 plus interleukin 12 changes immunoeffector mechanisms and suppresses helper T cell type 1 cytokine production induced by interleukin 12 alone Hum Gene Ther 2000 11: 127–138
Liu F, Song Y, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA Gene Ther 1999 6: 1258–1266
Zhang G, Budker V, Wolff JA . High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA Hum Gene Ther 1999 10: 1735–1737
Li J, et al . rAAV vector–mediated sarcogylcan gene transfer in a hamster model for limb girdle muscular dystrophy Gene Ther 1999 6: 74–82
Zhang G, Song YK, Liu D . Long-term expression of human alpha1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using a hydrodynamics-based procedure Gene Ther 2000 7: 1344–1349
Pham-Nguyen KB, et al . Role of NK and T cells in IL-12–induced anti-tumor response against hepatic colon carcinoma Int J Cancer 1999 81: 813–819
Fuji N, et al . Augmentation of local antitumor immunity in the liver by tumor vaccine modified to secrete murine interleukin 12 Gene Ther 1999 6: 1120–1127
Kurzawa H, et al . Recombinant interleukin 12 enhances cellular immune responses to vaccination only after a period of suppression Cancer Res 1998 58: 491–499
Fernandez NC, Levraud JP, Haddada H, Perricaudet M, Kourilsky P . High frequency of specific CD8+ T cells in the tumor and blood is associated with efficient local IL-12 gene therapy of cancer J Immunol 1999 162: 609–617
Caruso M, et al . Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma Proc Natl Acad Sci USA 1996 93: 11302–11306
Liu Z, et al . Hyperexpression of CD40 ligand (CD154) in inflammatory bowel disease and its contribution to pathogenic cytokine production J Immunol 1999 163: 4049–4057
Monahan PE, Samulski RJ . AAV vectors: is clinical success on the horizon? Gene Ther 2000 7: 24–30
Wang B, Li J, Xiao X . From the cover: adeno-associated virus vector carrying human minidystrophin genes effectively ameliorates muscular dystrophy in mdx mouse model Proc Natl Acad Sci USA 2000 97: 13714–13719
Acknowledgements
The authors thank Michael Y. Xiao for critical reading and editing of English. This work is supported, in part, by a grant from the State Key Basic Research Program in China (G1998051211).
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Wang, Z., Qiu, SJ., Ye, SL. et al. Combined IL-12 and GM-CSF gene therapy for murine hepatocellular carcinoma. Cancer Gene Ther 8, 751–758 (2001). https://doi.org/10.1038/sj.cgt.7700375
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DOI: https://doi.org/10.1038/sj.cgt.7700375
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