International Journal of Cancer Management

Published by: Kowsar

Combined Interleukin 12 and Granulocyte-macrophage Colony-stimulating Factor Gene Therapy Synergistically Suppresses Tumor Growth in the Murine Fibrosarcoma

Saiedeh Razi Soofiyani 1 , Farzaneh Lotfipour 2 , Tohid Kazemi 1 , Akbar Mohammad Hoseini 1 , Dariush Shanehbandi 1 , Leila Mohammadnejad 3 , Behzad Baradaran 1 , * and Somayeh Hallaj-Nezhadi 2 , **
Authors Information
1 Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
2 Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
3 Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Corresponding Authors:
Article information
  • International Journal of Cancer Management: October 2017, 10 (10); e8462
  • Published Online: October 31, 2017
  • Article Type: Research Article
  • Received: August 26, 2016
  • Revised: December 16, 2016
  • Accepted: September 1, 2017
  • DOI: 10.5812/ijcm.8462

How to Cite: Razi Soofiyani S, Lotfipour F, Kazemi T, Mohammad Hoseini A, Shanehbandi D, et al. Combined Interleukin 12 and Granulocyte-macrophage Colony-stimulating Factor Gene Therapy Synergistically Suppresses Tumor Growth in the Murine Fibrosarcoma, Int J Cancer Manag. 2017 ; 10(10):e8462. doi: 10.5812/ijcm.8462.

Copyright © 2017, Cancer Research Center (CRC), Shahid Beheshti University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background
2. Methods
3. Results
4. Discussion
  • 1. Bramante S, Koski A, Kipar A, Diaconu I, Liikanen I, Hemminki O, et al. Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans. Int J Cancer. 2014;135(3):720-30. doi: 10.1002/ijc.28696. [PubMed: 24374597].
  • 2. Helmy KY, Patel SA, Nahas GR, Rameshwar P. Cancer immunotherapy: accomplishments to date and future promise. Ther Deliv. 2013;4(10):1307-20. doi: 10.4155/tde.13.88. [PubMed: 24116914].
  • 3. Zigler M, Shir A, Levitzki A. Targeted cancer immunotherapy. Curr Opin Pharmacol. 2013;13(4):504-10. doi: 10.1016/j.coph.2013.04.003. [PubMed: 23648271].
  • 4. Razi Soofiyani S, Baradaran B, Lotfipour F, Kazemi T, Mohammadnejad L. Gene therapy, early promises, subsequent problems, and recent breakthroughs. Adv Pharm Bull. 2013;3(2):249-55. doi: 10.5681/apb.2013.041. [PubMed: 24312844].
  • 5. Ohno M, Natsume A, Wakabayashi T. Cytokine therapy. Adv Exp Med Biol. 2012;746:86-94. doi: 10.1007/978-1-4614-3146-6_7. [PubMed: 22639161].
  • 6. Pellegrini M, Mak TW, Ohashi PS. Fighting cancers from within: augmenting tumor immunity with cytokine therapy. Trends Pharmacol Sci. 2010;31(8):356-63. doi: 10.1016/ [PubMed: 20561689].
  • 7. Gutierrez-Ortega A, Sandoval-Montes C, de Olivera-Flores TJ, Santos-Argumedo L, Gomez-Lim MA. Expression of functional interleukin-12 from mouse in transgenic tomato plants. Transgenic Res. 2005;14(6):877-85. doi: 10.1007/s11248-005-1464-8. [PubMed: 16315093].
  • 8. Xu D, Gu P, Pan PY, Li Q, Sato AI, Chen SH. NK and CD8+ T cell-mediated eradication of poorly immunogenic B16-F10 melanoma by the combined action of IL-12 gene therapy and 4-1BB costimulation. Int J Cancer. 2004;109(4):499-506. doi: 10.1002/ijc.11696. [PubMed: 14991570].
  • 9. Toda M, Martuza RL, Rabkin SD. Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus-based cancer vaccine. Gene Ther. 2001;8(4):332-9. doi: 10.1038/ [PubMed: 11313808].
  • 10. Xu M, Mizoguchi I, Morishima N, Chiba Y, Mizuguchi J, Yoshimoto T. Regulation of antitumor immune responses by the IL-12 family cytokines, IL-12, IL-23, and IL-27. Clin Dev Immunol. 2010;2010. doi: 10.1155/2010/832454. [PubMed: 20885915].
  • 11. Razi Soofiyani S, Kazemi T, Lotfipour F, Mohammad Hosseini A, Shanehbandi D, Hallaj Nezhadi S, et al. Gene therapy with IL-12 induced enhanced anti tumor activity in fibrosarcoma mouse model. Artif Cells Nanomed Biotechnol. 2016;44(8):1988-93. doi: 10.3109/21691401.2015.1129618. [PubMed: 26759095].
  • 12. 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(1):83-90. doi: 10.1038/sj.cgt.7700083. [PubMed: 10678360].
  • 13. Suzuki R, Namai E, Oda Y, Nishiie N, Otake S, Koshima R, et al. Cancer gene therapy by IL-12 gene delivery using liposomal bubbles and tumoral ultrasound exposure. J Control Release. 2010;142(2):245-50. doi: 10.1016/j.jconrel.2009.10.027. [PubMed: 19883708].
  • 14. Wang Z, Qiu SJ, Ye SL, Tang ZY, Xiao X. Combined IL-12 and GM-CSF gene therapy for murine hepatocellular carcinoma. Cancer Gene Ther. 2001;8(10):751-8. doi: 10.1038/sj.cgt.7700375. [PubMed: 11687898].
  • 15. Chang CJ, Chen YH, Huang KW, Cheng HW, Chan SF, Tai KF, et al. Combined GM-CSF and IL-12 gene therapy synergistically suppresses the growth of orthotopic liver tumors. Hepatology. 2007;45(3):746-54. doi: 10.1002/hep.21560. [PubMed: 17326190].
  • 16. Wei F, Wang H, Zhang J, Chen X, Li C, Huang Q. Pharmacokinetics of combined gene therapy expressing constitutive human GM-CSF and hyperthermia-regulated human IL-12. J Exp Clin Cancer Res. 2013;32:5. doi: 10.1186/1756-9966-32-5. [PubMed: 23352035].
  • 17. Hamilton JA, Anderson GP. GM-CSF Biology. Growth Factors. 2004;22(4):225-31. doi: 10.1080/08977190412331279881. [PubMed: 15621725].
  • 18. Shi Y, Liu CH, Roberts AI, Das J, Xu G, Ren G, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res. 2006;16(2):126-33. doi: 10.1038/ [PubMed: 16474424].
  • 19. Hamilton JA. GM-CSF in inflammation and autoimmunity. Trends Immunol. 2002;23(8):403-8. [PubMed: 12133803].
  • 20. Unger EC, Hersh E, Vannan M, Matsunaga TO, McCreery T. Local drug and gene delivery through microbubbles. Prog Cardiovasc Dis. 2001;44(1):45-54. doi: 10.1053/pcad.2001.26443. [PubMed: 11533926].
  • 21. Garren H, Ruiz PJ, Watkins TA, Fontoura P, Nguyen LVT, Estline ER. Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway. Immunity. 2001;15(1):15-22. [PubMed: 11485734].
  • 22. Holder JW, Elmore E, Barrett JC. Gap junction function and cancer. Cancer Res. 1993;53(15):3475-85. [PubMed: 8393376].
  • 23. Freeman SM, Ramesh R, Marrogi AJ. Immune system in suicide-gene therapy. Lancet. 1997;349(9044):2-3. doi: 10.1016/S0140-6736(97)22001-5. [PubMed: 8988108].
  • 24. Rakhmilevich AL, Janssen K, Turner J, Culp J, Yang NS. Cytokine gene therapy of cancer using gene gun technology: superior antitumor activity of interleukin-12. Hum Gene Ther. 1997;8(11):1303-11. doi: 10.1089/hum.1997.8.11-1303. [PubMed: 9295125].
  • 25. Helms MW, Prescher JA, Cao YA, Schaffert S, Contag CH. IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy. Cancer Immunol Immunother. 2010;59(9):1325-34. doi: 10.1007/s00262-010-0860-y. [PubMed: 20532883].
  • 26. Del Vecchio M, Bajetta E, Canova S, Lotze MT, Wesa A, Parmiani G, et al. Interleukin-12: biological properties and clinical application. Clin Cancer Res. 2007;13(16):4677-85. doi: 10.1158/1078-0432.CCR-07-0776. [PubMed: 17699845].
  • 27. Leonard JP, Sherman ML, Fisher GL, Buchanan LJ, Larsen G, Atkins MB, et al. Effects of single-dose interleukin-12 exposure on interleukin-12-associated toxicity and interferon-gamma production. Blood. 1997;90(7):2541-8. [PubMed: 9326219].
  • 28. Berraondo P, Prieto J, Gonzalez-Aseguinolaza G. Advances in interleukin-12 gene therapy for acquired liver diseases. Curr Gene Ther. 2009;9(2):62-71. [PubMed: 19355864].
  • 29. Colombo MP, Vagliani M, Spreafico F, Parenza M, Chiodoni C, Melani C, et al. Amount of interleukin 12 available at the tumor site is critical for tumor regression. Cancer Res. 1996;56(11):2531-4. [PubMed: 8653692].
  • 30. Pertl U, Luster AD, Varki NM, Homann D, Gaedicke G, Reisfeld RA, et al. IFN-gamma-inducible protein-10 is essential for the generation of a protective tumor-specific CD8 T cell response induced by single-chain IL-12 gene therapy. J Immunol. 2001;166(11):6944-51. [PubMed: 11359856].
  • 31. Tare NS, Bowen S, Warrier RR, Carvajal DM, Benjamin WR, Riley JH, et al. Administration of recombinant interleukin-12 to mice suppresses hematopoiesis in the bone marrow but enhances hematopoiesis in the spleen. J Interferon Cytokine Res. 1995;15(4):377-83. doi: 10.1089/jir.1995.15.377. [PubMed: 7627813].
  • 32. Cohen J. IL-12 deaths: explanation and a puzzle. Science. 1995;270(5238):908. [PubMed: 7481785].
  • 33. Qin Z, Schwartzkopff J, Pradera F, Kammertoens T, Seliger B, Pircher H, et al. A critical requirement of interferon gamma-mediated angiostasis for tumor rejection by CD8+ T cells. Cancer Res. 2003;63(14):4095-100. [PubMed: 12874012].
  • 34. Li S, Xia X, Mellieon FM, Liu J, Steele S. Candidate genes associated with tumor regression mediated by intratumoral IL-12 electroporation gene therapy. Mol Ther. 2004;9(3):347-54. doi: 10.1016/j.ymthe.2003.11.022. [PubMed: 15006601].
  • 35. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother. 2015;38(1):1-11. doi: 10.1097/CJI.0000000000000062. [PubMed: 25415283].
  • 36. Yamazaki M, Straus FH, Messina M, Robinson BG, Takeda T, Hashizume K, et al. Adenovirus-mediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma. Cancer Gene Ther. 2004;11(1):8-15. doi: 10.1038/sj.cgt.7700636. [PubMed: 14681722].
  • 37. Choi KJ, Zhang SN, Choi IK, Kim JS, Yun CO. Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF. Gene Ther. 2012;19(7):711-23. doi: 10.1038/gt.2011.125. [PubMed: 21993173].
  • 38. Miguel A, Herrero MJ, Sendra L, Botella R, Algas R, Sanchez M, et al. Comparative antitumor effect among GM-CSF, IL-12 and GM-CSF+IL-12 genetically modified tumor cell vaccines. Cancer Gene Ther. 2013;20(10):576-81. doi: 10.1038/cgt.2013.54. [PubMed: 23969885].
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