Abstract
We report in a murine model of acute lymphoid leukemia L1210 the potent antitumor efficiency of a combinatorial delivery of pro-IL-18 gene modified L1210 (Lp18) and IL-1β converting enzyme (ICE) gene modified L1210 (LpICE). Live leukemia cells Lp18 or Lp18 plus LpICE showed apparently reduced leukemogenicity with a survival rate of 40 or 50% at 50 days after intraperitoneal (i.p.) inoculation of a lethal dose of cells, respectively. Combination of Lp18 and LpICE was capable of inhibiting accumulation of bloody ascites, synergistically superior to Lp18 or LpICE alone. All surviving mice were rechallenged with parental L1210 cells at day 50, and all survived up to day 80, suggesting that gene-modified cells induced immune protection. Moreover, NK cytotoxicity and CTL activity were both enhanced in mice injected with Lp18, especially Lp18 plus LpICE. Levels of IFN-γ were not altered significantly by inoculation of Lp18 or Lp18 plus LpICE. Our results demonstrate that IL-18 is a useful candidate gene in gene therapy of lymphoma or lymphoid leukemia, and ex vivo combinatorial delivery of Lp18 plus LpICE either as a single approach or as an adjunct to concomitant radiotherapy or chemotherapy, may be more efficient in a situation of minimal residual disease.
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Wierda WG, Kipps TJ . Gene therapy of hematologic malignancies. Semin Oncol 2000; 27: 502–511.
Schmidt-Wolf GD, Schmidt-Wolf IG . Gene therapy for hematological malignancies. Clin Exp Med 2003; 3: 4–14.
Whiteside TL, Gooding W . Immune monitoring of human gene therapy trials: potential application to leukemia and lymphoma. Blood Cells Mol Dis 2003; 31: 63–71.
Ajiki T, Murakami T, Kobayashi Y, Hakamata Y, Wang J, Inoue S et al. Long-lasting gene expression by particle-mediated intramuscular transfection modified with bupivacaine: combinatorial gene therapy with IL-12 and IL-18 cDNA against rat sarcoma at a distant site. Cancer Gene Ther 2003; 10: 318–329.
Tamura T, Nishi T, Goto T, Takeshima H, Ushio Y, Sakata T . Combination of IL-12 and IL-18 of electro-gene therapy synergistically inhibits tumor growth. Anticancer Res 2003; 23: 1173–1179.
Ma HL, Whitters MJ, Konz RF, Senices M, Young DA, Grusby MJ et al. IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-gamma. J Immunol 2003; 171: 608–615.
Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW et al. Antitumor and antimetastatic activity of IL-23. J Immunol 2003; 171: 600–607.
Ziller C, Stoeckel F, Boon L, Haegel-Kronenberger H . Transient blocking of both B7.1 (CD80) and B7.2 (CD86) in addition to CD40-CD40L interaction fully abrogates the immune response following systemic injection of adenovirus vector. Gene Ther 2002; 9: 537–546.
Ando H, Saio M, Ohe N, Tamakawa N, Yu H, Nakayama T et al. B7.1 immunogene therapy effectively activates CD(4+) tumor-infiltrating lymphocytes in the central nervous system in comparison with B7.2 gene therapy. Int J Oncol 2002; 20: 807–812.
Tong AW, Stone MJ . Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther 2003; 10: 1–13.
Penninger JM, Wen T, Timms E, Potter J, Wallace VA, Matsuyama T et al. Spontaneous resistance to acute T cell leukaemias in TCRVγ1.1Jγ4Cγ4 transgenic mice. Nature 1995; 375: 241–244.
Stripecke R, Levine AM, Pullarkat V, Cardoso AA . Immunotherapy with acute leukemia cells modified into antigen-presenting cells: ex vivo culture and gene transfer methods. Leukemia 2002; 16: 1974–1983.
Stripecke R, Skelton DC, Pattengale PK, Shimada H, Kohn DB . Combination of CD80 and granulocyte-macrophage colony-stimulating factor coexpression by a leukemia cell vaccine: preclinical studies in a murine model recapitulating Philadelphia chromosome-positive acute lymphoblastic leukemia. Hum Gene Ther 1999; 10: 2109–2122.
Takahashi T, Hirano N, Takahashi T, Chiba S, Yazaki Y, Hirai H . Immunogene therapy against mouse leukemia using B7 molecules. Cancer Gene Ther 2000; 7: 144–150.
Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ . CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 2000; 96: 2917–2924.
Takahashi S, Rousseau RF, Yotnda P, Mei Z, Dotti G, Rill D, Hurwitz R et al. Autologous antileukemic immune response induced by chronic lymphocytic leukemia B cells expressing the CD40 ligand and interleukin 2 transgenes. Hum Gene Ther 2001; 12: 659–670.
Anether G, Marschitz I, Tinhofer I, Greil R . Interleukin-15 as a potential costimulatory cytokine in CD154 gene therapy of chronic lymphocytic leukemia. Blood 2002; 99: 722–723, (letter).
Chu P, Deforce D, Pedersen IM, Kim Y, Kitada S, Reed JC et al. Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 2002; 99: 3854–3859.
Dunussi-Joannopoulos K, Runyon K, Erickson J, Schaub RG, Hawley RG, Leonard JP . Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very potent therapeutic and long-lasting protective immunity. Blood 1999; 94: 4263–4273.
Xu YX, Gao X, Janakiraman N, Chapman RA, Gautam SC . IL-12 gene therapy of leukemia with hematopoietic progenitor cells without the toxicity of systemic IL-12 treatment. Clin Immunol 2001; 98: 180–189.
Saudemont A, Buffenoir G, Denys A, Desreumaux P, Jouy N, Hetuin D et al. Gene transfer of CD154 and IL12 cDNA induces an anti-leukemic immunity in a murine model of acute leukemia. Leukemia 2002; 16: 1637–1644.
Reddy P, Teshima T, Hildebrandt G, Duffner U, Maeda Y, Cooke KR et al. Interleukin 18 preserves a perforin-dependent graft-versus-leukemia effect after allogeneic bone marrow transplantation. Blood 2002; 100: 3429–3431.
Reddy P, Teshima T, Hildebrandt G, Williams DL, Liu C, Cooke KR et al. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood 2003; 101: 2877–2885.
Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995; 378: 88–91.
Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming MA et al. Activation of interferon-γ inducing factor mediated by interleukin-1beta converting enzyme. Science 1997; 275: 206–209.
Vidal-Vanaclocha F, Fantuzzi G, Mendoza L, Fuentes AM, Anasagasti MJ, Martin J et al. IL-18 regulates IL-1beta-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1. Proc Natl Acad Sci USA 2000; 97: 734–739.
Iwasaki T, Yamashita K, Tsujimura T, Kashiwamura S, Tsutsui H, Kaisho T et al. Interleukin-18 inhibits osteolytic bone metastasis by human lung cancer cells possibly through suppression of osteoclastic bone-resorption in nude mice. J Immunother 2002; 25 (Suppl 1): S52–S60.
Ju DW, Tao Q, Lou G, Bai M, He L, Yang Y et al. Interleukin 18 transfection enhances antitumor immunity induced by dendritic cell-tumor cell conjugates. Cancer Res 2001; 61: 3735–3740.
Tatsumi T, Gambotto A, Robbins PD, Storkus WJ . Interleukin 18 gene transfer expands the repertoire of antitumor Th1-type immunity elicited by dendritic cell-based vaccines in association with enhanced therapeutic efficacy. Cancer Res 2002; 62: 5853–5858.
Tanaka F, Hashimoto W, Robbins PD, Lotze MT, Tahara H . Therapeutic and specific antitumor immunity induced by co-administration of immature dendritic cells and adenoviral vector expressing biologically active IL-18. Gene Ther 2002; 9: 1480–1486.
Osaki T, Hashimoto W, Gambotto A, Okamura H, Robbins PD, Kurimoto M et al. Potent antitumor effects mediated by local expression of the mature form of the interferon-γ inducing factor, interleukin-18 (IL-18). Gene Ther 1999; 6: 808–815.
Oshikawa K, Shi F, Rakhmilevich AL, Sondel PM, Mahvi DM, Yang NS . Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1beta converting enzyme cDNA. Proc Natl Acad Sci USA 1999; 96: 13351–13356.
Tasaki K, Yoshida Y, Maeda T, Miyauchi M, Kawamura K, Takenaga K et al. Protective immunity is induced in murine colon carcinoma cells by the expression of interleukin-12 or interleukin-18, which activate type 1 helper T cells. Cancer Gene Ther 2000; 7: 247–254.
Ju DW, Yang Y, Tao Q, Song WG, He L, Chen G et al. Interleukin-18 gene transfer increases antitumor effects of suicide gene therapy through efficient induction of antitumor immunity. Gene Ther 2000; 7: 1672–1679.
Wang Q, Yu H, Ju DW, He L, Pan JP, Xia DJ et al. Intratumoral IL-18 gene transfer improves therapeutic efficacy of antibody-targeted superantigen in established murine melanoma. Gene Ther 2001; 8: 542–550.
Kishida T, Asada H, Satoh E, Tanaka S, Shinya M, Hirai H et al. In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice. Gene Ther 2001; 8: 1234–1240.
Yoshimura K, Hazama S, Iizuka N, Yoshino S, Yamamoto K, Muraguchi M et al. Successful immunogene therapy using colon cancer cells (colon 26) transfected with plasmid vector containing mature interleukin-18 cDNA and the Igkappa leader sequence. Cancer Gene Ther 2001; 8: 9–16.
Liu Y, Huang H, Saxena A, Xiang J . Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors. Cancer Gene Ther 2002; 9: 533–542.
Micallef MJ, Tanimoto T, Kohno K, Ikeda M, Kurimoto M . Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma. Cancer Res 1997; 57: 4557–4563.
Yamanaka K, Hara I, Nagai H, Miyake H, Gohji K, Micallef MJ et al. Synergistic antitumor effects of interleukin-12 gene transfer and systemic administration of interleukin-18 in a mouse bladder cancer model. Cancer Immunol Immunother 1999; 48: 297–302.
Hara I, Nagai H, Miyake H, Yamanaka K, Hara S, Micallef MJ et al. Effectiveness of cancer vaccine therapy using cells transduced with the interleukin-12 gene combined with systemic interleukin-18 administration. Cancer Gene Ther 2000; 7: 83–90.
Son YI, Dallal RM, Lotze MT . Combined treatment with interleukin-18 and low-dose interleukin-2 induced regression of a murine sarcoma and memory response. J Immunother 2003; 26: 234–240.
Zhang B, Wang Y, Zheng GG, Ma XT, Li G, Zhang FK et al. Clinical significance of IL-18 over-expression in AML. Leukemia Res 2002; 26: 887–892.
Wang Y, Zheng GG, Wu KF, Li G, Rao Q . Construction of macrophage colony-stimulating factor receptor DNA vaccine. Haematologica 2001; 86: 1219–1220.
Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A et al. Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN-γ production. Nature 1997; 386: 619–623.
Kimura F, Douzono M, Ohta J, Morita T, Ikeda K, Nakamura Y et al. Augmentation of antitumor immunity using genetically M-CSF-expressing L1210 cells. Exp Hematol 1996; 24: 360–363.
Agha-Mohammadi S, Lotze MT . Immunomodulation of cancer: potential use of selectively replicating agents. J Clin Invest 2000; 105: 1173–1176.
Osaki T, Peron JM, Cai Q, Okamura H, Robbins PD, Kurimoto M et al. IFN-γ-inducing factor/IL-18 administration mediates IFN-γ- and IL-12-independent antitumor effects. J Immunol 1998; 160: 1742–1749.
Fukumoto H, Nishio M, Nishio K, Heike Y, Arioka H, Kurokawa H et al. Interferon-gamma-inducing factor gene transfection into Lewis lung carcinoma cells reduces tumorigenicity in vivo. Jpn J Cancer Res 1997; 88: 501–505.
Akamatsu S, Arai N, Hanaya T, Arai S, Tanimoto T, Fujii M et al. Antitumor activity of interleukin-18 against the murine T-cell leukemia/lymphoma EL-4 in syngeneic mice. J Immunother 2002; 25: S28–S34.
Arai N, Akamatsu S, Arai S, Toshimori Y, Hanaya T, Tanimoto T et al. Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-γ in vivo. J Interferon Cytokine Res 2000; 20: 217–224.
Zhang B, Cao ZY, Wu KF, Lin YM . Expression of IL-18 and its receptor in leukemia cells. Leukemia Res 2003; 27: 813–822.
Coughlin CM, Salhany KE, Wysocka M, Aruga E, Kurzawa H, Chang AE et al. Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest 1998; 101: 1441–1452.
Cao R, Farnebo J, Kurimoto M, Cao Y . Interleukin-18 acts as an angiogenesis and tumor suppressor. FASEB J 1999; 13: 2195–2202.
Acknowledgements
This work was supported by the Climbing Program granted by The Ministry of Science and Technology of China (95-special-10) and the Tianjin Science and Technology Development program of China (003119311). Thanks to Ms. Yi-Qi Geng, Li-Li An, Min Wang, and Mrs Xiu-Jun Zhang, Ying-Hua Yang, Jun-Ming Zhao for their technical assistance. Thanks to Professor Sheng-Guo You for kindly providing L1210 and YAC-1 cells.
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Zhang, B., Wu, KF., Lin, YM. et al. Gene transfer of pro-IL-18 and IL-1β converting enzyme cDNA induces potent antitumor effects in L1210 cells. Leukemia 18, 817–825 (2004). https://doi.org/10.1038/sj.leu.2403320
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DOI: https://doi.org/10.1038/sj.leu.2403320
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