Abstract
Interleukin-12 has been a promising candidate for cancer treatment for over 20 years. And from its infamous start, the gene electrotransfer delivery has regained assurance of the safe and effective use of interleukin-12 in cancer treatment. Here, basic facts about interleukin-12 are presented with a focus on its antitumor action and the benefit of electrotransfer delivery. In veterinary oncology, interleukin-12 gene electrotransfer has been used in preclinical and clinical studies on dogs for over 10 years. In this chapter studies of interleukin-12 immunotherapy alone or in combination with electrochemotherapy or surgery in different types of dogs’ tumors are presented with emphasis on the antitumor effect on primary tumors as well as on distant metastasis. Also, the impact of interleukin-12 gene electrotransfer on the immune system is discussed as well as the safety of the procedure and possible improvement of the procedure.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Achyut BR, Arbab AS (2016) Myeloid cell signatures in tumor microenvironment predicts therapeutic response in cancer. Onco Targets Ther 9:1047–1055. https://doi.org/10.2147/OTT.S102907
Atkins MB, Robertson MJ, Gordon M et al (1997) Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res 3(3):409–417
Belehradek J, Barski G, Thonier M (1972) Evolution of cell-mediated antitumor immunity in mice bearing a syngeneic chemically induced tumor. Influence of tumor growth, surgical removal and treatment with irradiated tumor cells. Int J Cancer 9:461–469. https://doi.org/10.1002/ijc.2910090302
Bhatia S, Longino NV, Miller NJ et al (2020) Intratumoral delivery of plasmid IL12 via electroporation leads to regression of injected and noninjected tumors in Merkel cell carcinoma. Clin Cancer Res 26:598–607. https://doi.org/10.1158/1078-0432.CCR-19-0972
Buttner M, Belke-Louis G, Rziha HJ et al (1998) Detection, cDNA cloning and sequencing of canine interleukin 12. Cytokine 10:241–248. https://doi.org/10.1006/cyto.1997.0284
Canton DA, Shirley S, Wright J et al (2017) Melanoma treatment with intratumoral electroporation of tavokinogene telseplasmid (pIL-12, tavokinogene telseplasmid). Immunotherapy 9:1309–1321. https://doi.org/10.2217/imt-2017-0096
Cemazar M, Ambrozic Avgustin J, Pavlin D et al (2016) Efficacy and safety of electrochemotherapy combined with peritumoral IL-12 gene electrotransfer of canine mast cell tumours. Vet Comp Oncol 15(2):641–654. https://doi.org/10.1111/vco.12208
Cemazar M, Jarm T, Sersa G (2010) Cancer electrogene therapy with interleukin-12. Curr Gene Ther 10:300–311
Cemazar M, Sersa G, Pavlin D, Tozon N (2011) Intramuscular IL-12 Electrogene therapy for treatment of spontaneous canine tumors. In: Yongping Y (ed) targets in gene therapy, IntechOpen, doi: https://doi.org/10.5772/20734. https://www.intechopen.com/books/targets-in-gene-therapy/intramuscular-il-12-electrogene-therapy-for-treatment-of-spontaneous-canine-tumors. Accessed 3 May 2020
Chávez-Galán L, Olleros ML, Vesin D, Garcia I (2015) Much more than M1 and M2 macrophages, there are also CD169(+) and TCR(+) macrophages. Front Immunol 6:263. https://doi.org/10.3389/fimmu.2015.00263
Chuang T-F, Lee S-C, Liao K-W et al (2009) Electroporation-mediated IL-12 gene therapy in a transplantable canine cancer model. Int J Cancer 125:698–707. https://doi.org/10.1002/ijc.24418
Cicchelero L, Denies S, Haers H et al (2017) Intratumoural interleukin 12 gene therapy stimulates the immune system and decreases angiogenesis in dogs with spontaneous cancer. Vet Comp Oncol 15(4):1187–1205. https://doi.org/10.1111/vco.12255
Cutrera J, King G, Jones P et al (2015a) Safety and efficacy of tumor-targeted interleukin 12 gene therapy in treated and non-treated, metastatic lesions. Curr Gene Ther 15:44–54
Cutrera J, King G, Jones P et al (2015b) Safe and effective treatment of spontaneous neoplasms with interleukin 12 electro-chemo-gene therapy. J Cell Mol Med 19:664–675. https://doi.org/10.1111/jcmm.12382
Cutrera J, Torrero MN, Shiomitsu K et al (2008) Intratumoral bleomycin and IL-12 electrochemogenetherapy for treating head and neck tumors in dogs. Methods Mol Biol 423:319–325. https://doi.org/10.1007/978-1-59745-194-9_24
Del Vecchio M, Bajetta E, Canova S et al (2007) Interleukin-12: biological properties and clinical application. Clin Cancer Res 13:4677–4685. https://doi.org/10.1158/1078-0432.CCR-07-0776
Ferraro B, Morrow MP, Hutnick NA et al (2011) Clinical applications of DNA vaccines: current progress. Clin Infect Dis 53:296–302. https://doi.org/10.1093/cid/cir334
Finn OJ (2012) Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol 23(Suppl 8):viii6–viii9. https://doi.org/10.1093/annonc/mds256
Gollob JA, Mier JW, Veenstra K et al (2000) Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-γ induction is associated with clinical response. Clin Cancer Res 6(5):1678–1692
Gonzalez-Gugel E, Saxena M, Bhardwaj N (2016) Modulation of innate immunity in the tumor microenvironment. Cancer Immunol Immunother 65:1261–1268
Gothelf A, Gehl J (2012) What you always needed to know about electroporation based DNA vaccines. Hum Vaccin Immunother 8:1694–1702. https://doi.org/10.4161/Hv.22062
Hanna E, Zhang X, Woodlis J et al (2001) Intramuscular electroporation delivery of IL-12 gene for treatment of squamous cell carcinoma located at distant site. Cancer Gene Ther 8:151–157. https://doi.org/10.1038/sj.cgt.7700287
Kim J, Kim J, Bae JS (2016) ROS homeostasis and metabolism: a critical liaison for cancer therapy. Exp Mol Med 48(11):e269. https://doi.org/10.1038/emm.2016.119
Kishida T, Asada H, Itokawa Y et al (2003) Electrochemo-gene therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice. Mol Ther 8:738–745
Kobayashi M, Fitz L, Ryan M et al (1989) Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med 170(3):827–845. https://doi.org/10.1084/jem.170.3.827
Lampreht Tratar U, Kos S, Kamensek U et al (2018) Antitumor effect of antibiotic resistance gene-free plasmids encoding interleukin-12 in canine melanoma model. Cancer Gene Ther 25(9–10):260–273. https://doi.org/10.1038/s41417-018-0014-5
Lampreht Tratar U, Loiacono L, Cemazar M et al (2017) Gene Electrotransfer of plasmid-encoding IL-12 recruits the M1 macrophages and antigen-presenting cells inducing the eradication of aggressive B16F10 murine melanoma. Mediat Inflamm 2017:5285890. https://doi.org/10.1155/2017/5285890
Lasek W, Zagożdżon R, Jakobisiak M (2014) Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother 63:419–435. https://doi.org/10.1007/s00262-014-1523-1
Lenzi R, Rosenblum M, Verschraegen C et al (2002) Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Müllerian carcinoma, gastrointestinal primary malignancies, and mesothelioma. Clin Cancer Res 8(12):3686–3695
Leonard JP, Sherman ML, Fisher GL et al (1997) Effects of single-dose interleukin-12 exposure on interleukin-12 associated toxicity and interferon-γ production. Blood 90(7):2541–2548. https://doi.org/10.1182/blood.V90.7.2541
Li S, Zhang X, Xia X (2002) Regression of tumor growth and induction of long-term antitumor memory by interleukin 12 electro-gene therapy. J Natl Cancer Inst 94:762–768. https://doi.org/10.1093/jnci/94.10.762
Lucas ML, Heller LC, Coppola D, Heller R (2002) IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol Ther 5:668–675. https://doi.org/10.1006/mthe.2002.0601
Martínez-Lostao L, Anel A, Pardo J (2015) How do cytotoxic lymphocytes kill Cancer cells? Clin Cancer Res 21(22):5047–5056. https://doi.org/10.1158/1078-0432.CCR-15-0685
Milevoj N, Tozon N, Licen S et al (2020) Health-related quality of life in dogs treated with electrochemotherapy and/or interleukin-12 gene electrotransfer. Vet Med Sci 6(3):290–298. https://doi.org/10.1002/vms3.232
Milevoj N, Tratar UL, Nemec A et al (2019) A combination of electrochemotherapy, gene electrotransfer of plasmid encoding canine IL-12 and cytoreductive surgery in the treatment of canine oral malignant melanoma. Res Vet Sci 122:40–49. https://doi.org/10.1016/j.rvsc.2018.11.001
Motzer RJ, Rakhit A, Schwartz LH et al (1998) Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res 4(5):1183–1191
Nemec A, Milevoj N, Lampreht Tratar U et al (2020) Electroporation-based treatments in small animal veterinary Oral and maxillofacial oncology. Front Vet Sci 7:575911. https://doi.org/10.3389/fvets.2020.575911
Owen LN (1980) TNM classification of tumours in domestic animals. World Health Organization. Veterinary public health unit & WHO collaborating Center for Comparative Oncology. Edited by L.N. Owen. World Health Organization. https://apps.who.int/iris/handle/10665/68618; Assessed on 26.10.2020
Passarelli A, Mannavola F, Stucci LS et al (2017) Immune system and melanoma biology: a balance between immunosurveillance and immune escape. Oncotarget 8(62):106132–106142. https://doi.org/10.18632/oncotarget.22190
Pavlin D, Cemazar M, Cor A et al (2011) Electrogene therapy with interleukin-12 in canine mast cell tumors. Radiol Oncol 45:31–39. https://doi.org/10.2478/v10019-010-0041-9
Pavlin D, Cemazar M, Kamensek U et al (2009) Local and systemic antitumor effect of intratumoral and peritumoral IL-12 electrogene therapy on murine sarcoma. Cancer Biol Ther 8:2114–2122
Pavlin D, Tozon N, Sersa G et al (2008) Efficient electrotransfection into canine muscle. Technol Cancer Res Treat 7(1):45–54. https://doi.org/10.1177/153303460800700106
Reed SD, Fulmer A, Buckholz J et al (2010) Bleomycin/interleukin-12 electrochemogenetherapy for treating naturally occurring spontaneous neoplasms in dogs. Cancer Gene Ther 17:571–578. https://doi.org/10.1038/cgt.2010.13
Robertson MJ, Cameron C, Atkins MB et al (1999) Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer. Clin Cancer Res 5(1):9–16
Salvadori C, Svara T, Rocchigiani G et al (2017) Effects of electrochemotherapy with cisplatin and peritumoral IL-12 gene electrotransfer on canine mast cell tumors: a histopathologic and immunohistochemical study. Radiol Oncol 51:286–294. https://doi.org/10.1515/raon-2017-0035
Schoenhaut DS, Chua AO, Wolitzky AG et al (1992) Cloning and expression of murine IL-12. J Immunol 148(11):3433–3440
Sedlar A, Dolinsek T, Markelc B et al (2012) Potentiation of electrochemotherapy by intramuscular IL-12 gene electrotransfer in murine sarcoma and carcinoma with different immunogenicity. Radiol Oncol 46:302–311. https://doi.org/10.2478/v10019-012-0044-9
Sedlar A, Kranjc S, Dolinsek T et al (2013) Radiosensitizing effect of intratumoral interleukin-12 gene electrotransfer in murine sarcoma. BMC Cancer 13:38. https://doi.org/10.1186/1471-2407-13-38
Sersa G, Teissie J, Cemazar M et al (2015) Electrochemotherapy of tumors as in situ vaccination boosted by immunogene electrotransfer. Cancer Immunol Immunother 64:1315–1327. https://doi.org/10.1007/s00262-015-1724-2
Shi G, Edelblute C, Arpag S et al (2018) IL-12 gene electrotransfer triggers a change in immune response within mouse tumors. Cancers (Basel). 10(12):E498. https://doi.org/10.3390/cancers10120498
Shirley SA, Lundberg CG, Li F et al (2015) Controlled gene delivery can enhance therapeutic outcome for cancer immune therapy for melanoma. Curr Gene Ther 15:32–43
Solensky R (2003) Hypersensitivity reactions to beta-lactam antibiotics. Clin Rev Allergy Immunol 24:201–220. https://doi.org/10.1385/criai:24:3:201
Stern AS, Podlaski FJ, Hulmes JD et al (1990) Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A 87(17):6808–6812. https://doi.org/10.1073/pnas.87.17.6808
Tevz G, Kranjc S, Cemazar M et al (2009) Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas. J Gene Med 11:1125–1137. https://doi.org/10.1002/jgm.1403
Vandermeulen G, Marie C, Scherman D, Préat V (2011) New generation of plasmid backbones devoid of antibiotic resistance marker for gene therapy trials. Mol Ther 19:1942–1949. https://doi.org/10.1038/mt.2011.182
Vandeven NA, Nghiem P (2016) Merkel cell carcinoma: an unusually immunogenic cancer proves ripe for immune therapy. J Oncol Pract 12(7):649–650. https://doi.org/10.1200/JOP.2016.014498
Vinay DS, Ryan EP, Pawelec G et al (2015) Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 35:S185–S198. https://doi.org/10.1016/j.semcancer.2015.03.004
Voest EE, Kenyon BM, O’reilly MS et al (1995) Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst 87(8):581–586. https://doi.org/10.1093/jnci/87.8.581
Wculek SK, Cueto FJ, Mujal AM et al (2020) Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol 20:7–24
Withrow SJ, Vail DM (2007) Specific malignancies in the small animal patient. In: Vail D (ed) Small Animal Clinical Oncology, 4th edn. Elsevier, Netherlands, pp 305–715
Wolf SF, Temple PA, Kobayashi M et al (1991) Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol 146(9):3074–3081
Yamashita YI, Shimada M, Hasegawa H et al (2001) Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61:1005–1012
Yang L, Zhang Y (2017) Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 10:58
Yarmush ML, Golberg A, Sersa G et al (2014) Electroporation-based technologies for medicine: principles, applications, and challenges. Annu Rev Biomed Eng 16:295–320. https://doi.org/10.1146/annurev-bioeng-071813-104622
Younes A, Pro B, Robertson MJ et al (2004) Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma and Hodgkin’s disease. Clin Cancer Res 10(16):5432–5438. https://doi.org/10.1158/1078-0432.CCR-04-0540
Acknowledgments
This work was financially supported by the Slovenian Research Agency Programs P3-0003 and P4-0220 and projects J3-6796 and J3-8202.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this chapter
Cite this chapter
Lampreht Tratar, U. et al. (2021). Interleukin-12 Gene Electrotransfer in Veterinary Oncology. In: Impellizeri, J.A. (eds) Electroporation in Veterinary Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-030-80668-2_11
Download citation
DOI: https://doi.org/10.1007/978-3-030-80668-2_11
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-80667-5
Online ISBN: 978-3-030-80668-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)