• Sonam Chopra Vytautas Magnus University, Kaunas
  • Saulius Satkauskas Vytautas Magnus University, Kaunas
Keywords: gene electrotransfer, electroporation, cytokine, cancer


Gene electrotransfer, which designates the combination of gene transfer and electroporation, is a physical method for transfecting genes into cells and tissues. Many reports for the utilization of this techniques in animals confirmed that gene electrotransfer is a safe and efficient method. One of the major advantages of electrogene therapy is that it does not result in systemic toxicity. Gene electrotransfer (GET) of plasmids encoding cytokines has been shown to generate a potent anti-tumor effect. Delivery of plasmids encoding cytokines induces not only a local immune response but a systemic one as well.  Cytokines can be used to stimulate host inflammatory responses and immunity to cancers.  This review aims to summarize preclinically tested cytokine genes with the help of electroporation for cancer treatment.


Antony, G. K., & Dudek, A. Z. (2010). Interleukin 2 in cancer therapy. Current Medicinal Chemistry, 17(29), 3297-3302. doi:BSP/CMC/E-Pub/ 207 [doi]

Baginska, J., Viry, E., Paggetti, J., Medves, S., Berchem, G., Moussay, E., & Janji, B. (2013). The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Frontiers in Immunology, 4, 490. doi:10.3389/fimmu.2013.00490 [doi]

Bodles-Brakhop, A. M., Heller, R., & Draghia-Akli, R. (2009). Electroporation for the delivery of DNA-based vaccines and immunotherapeutics: Current clinical developments. Molecular Therapy: The Journal of the American Society of Gene Therapy, 17(4), 585-592. doi:10.1038/mt.2009.5 [doi]

Bonehill, A., Tuyaerts, S., Van Nuffel, A. M., Heirman, C., Bos, T. J., Fostier, K., . . . Thielemans, K. (2008). Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. Molecular Therapy : The Journal of the American Society of Gene Therapy, 16(6), 1170-1180. doi:10.1038/mt.2008.77 [doi]

Burgain-Chain, A., & Scherman, D. (2013). DNA electrotransfer: An effective tool for gene therapy. In F. Martin (Ed.), Gene therapy (). Rijeka: InTech. doi:10.5772/52528 Retrieved from https://doi.org/10.5772/52528

Daud, A. I., DeConti, R. C., Andrews, S., Urbas, P., Riker, A. I., Sondak, V. K., . . . Heller, R. (2008). Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 26(36), 5896-5903. doi:10.1200/JCO.2007.15.6794 [doi]

Daud, A., Algazi, A. P., Ashworth, M. T., Fong, L., Lewis, J., Chan, S. E., . . . Bhatia, S. (2014). Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. Jco, 32(15), 9025-9025. doi:10.1200/jco.2014.32.15_suppl.9025

Dranoff, G. (2004). Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews.Cancer, 4(1), 11-22. doi:10.1038/nrc1252 [doi]

Favard, C., Dean, D. S., & Rols, M. P. (2007). Electrotransfer as a non viral method of gene delivery. Current Gene Therapy, 7(1), 67-77.

Ferrantini, M., & Belardelli, F. (2000). Gene therapy of cancer with interferon: Lessons from tumor models and perspectives for clinical applications doi:https://doi.org/10.1006/scbi.2000.0333

Floros, T., & Tarhini, A. A. (2015). Anticancer cytokines: Biology and clinical effects of interferon-alpha2, interleukin (IL)-2, IL-15, IL-21, and IL-12. Seminars in Oncology, 42(4), 539-548. doi:10.1053/j.seminoncol.2015.05.015 [doi]

Heller, L. C., & Heller, R. (2006). In vivo electroporation for gene therapy. Human Gene Therapy, 17(9), 890-897. doi:10.1089/hum.2006.17.890 [doi]

Heller, R., & Heller, L. C. (2015). Gene electrotransfer clinical trials. Advances in Genetics, 89, 235-262. doi:10.1016/bs.adgen.2014.10.006 [doi]

Jiang, J., Yamato, E., & Miyazaki, J. (2001). Intravenous delivery of naked plasmid DNA for in vivo cytokine expression. Biochemical and Biophysical Research Communications, 289(5), 1088-1092. doi:10.1006/bbrc.2001.6100 [doi]

Kalb, M. L., Glaser, A., Stary, G., Koszik, F., & Stingl, G. (2012). TRAIL(+) human plasmacytoid dendritic cells kill tumor cells in vitro: Mechanisms of imiquimod- and IFN-alpha-mediated antitumor reactivity. Journal of Immunology (Baltimore, Md.: 1950), 188(4), 1583-1591. doi:10.4049/jimmunol.1102437 [doi]

Kanduser, M., Miklavcic, D., & Pavlin, M. (2009). Mechanisms involved in gene electrotransfer using high- and low-voltage pulses--an in vitro study. Bioelectrochemistry (Amsterdam, Netherlands), 74(2), 265-271. doi:10.1016/j.bioelechem.2008.09.002 [doi]

Kishida, T., Asada, H., Itokawa, Y., Yasutomi, K., Shin-Ya, M., Gojo, S., . . . Mazda, O. (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. Molecular Therapy : The Journal of the American Society of Gene Therapy, 8(5), 738-745. doi:S1525-0016(03)00279-X [pii]

Kortylewski, M., Xin, H., Kujawski, M., Lee, H., Liu, Y., Harris, T., . . . Yu, H. (2009). Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell, 15(2), 114-123. doi:10.1016/j.ccr.2008.12.018 [doi]

Lucas, M. L., Heller, L., Coppola, D., & Heller, R. (2002). IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Molecular Therapy : The Journal of the American Society of Gene Therapy, 5(6), 668-675. doi:10.1006/mthe.2002.0601 [doi]

Marrero, B., Shirley, S., & Heller, R. (2014). Delivery of interleukin-15 to B16 melanoma by electroporation leads to tumor regression and long-term survival. Technology in Cancer Research & Treatment, 13(6), 551-560. doi:10.7785/tcrtexpress.2013.600252 [doi]

Miklavcic, D., Mali, B., Kos, B., Heller, R., & Sersa, G. (2014). Electrochemotherapy: From the drawing board into medical practice. Biomedical Engineering Online, 13(1), 29-925X-13-29. doi:10.1186/1475-925X-13-29 [doi]

Mir, L. M., Bureau, M. F., Rangara, R., Schwartz, B., & Scherman, D. (1998). Long-term, high level in vivo gene expression after electric pulse-mediated gene transfer into skeletal muscle. Comptes Rendus De L'Academie Des Sciences.Serie III, Sciences De La Vie, 321(11), 893-899. doi:S0764446999800031 [pii]

Neumann, E., Schaefer-Ridder, M., Wang, Y., & Hofschneider, P. H. (1982). Gene transfer into mouse lyoma cells by electroporation in high electric fields. The EMBO Journal, 1(7), 841-845.

Nishi, T., Yoshizato, K., Yamashiro, S., Takeshima, H., Sato, K., Hamada, K., . . . Ushio, Y. (1996). High-efficiency in vivo gene transfer using intraarterial plasmid DNA injection following in vivo electroporation. Cancer Research, 56(5), 1050-1055.

Okamura, H., Nagata, K., Komatsu, T., Tanimoto, T., Nukata, Y., Tanabe, F., . . . Fukuda, S. (1995). A novel costimulatory factor for gamma interferon induction found in the livers of mice causes endotoxic shock. Infection and Immunity, 63(10), 3966-3972.

Pizza, G., Severini, G., Menniti, D., De Vinci, C., & Corrado, F. (1984). Tumour regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. preliminary report. International Journal of Cancer, 34(3), 359-367.

Richards, J. M., Gonzalez, R., Schwarzenberger, P., Whitman, E., Stardal, K., Westhoff, C., . . . Selk, L. (2007). Phase I trial of IL-2 plasmid DNA with electroporation in metastatic melanoma. Jco, 25(18), 8578-8578. doi:10.1200/jco.2007.25.18_suppl.8578

Rols, M. P. (2008). Mechanism by which electroporation mediates DNA migration and entry into cells and targeted tissues. Methods in Molecular Biology (Clifton, N.J.), 423, 19-33. doi:10.1007/978-1-59745-194-9_2 [doi]

Rosenberg, S. A., Lotze, M. T., Muul, L. M., Leitman, S., Chang, A. E., Ettinghausen, S. E., . . . Vetto, J. T. (1985). Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. The New England Journal of Medicine, 313(23), 1485-1492. doi:10.1056/NEJM198512053132327 [doi]

Schmidt-Wolf, I. G., Finke, S., Trojaneck, B., Denkena, A., Lefterova, P., Schwella, N., . . . Huhn, D. (1999). Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. British Journal of Cancer, 81(6), 1009-1016. doi:10.1038/sj.bjc.6690800 [doi]

Shirley, S. A. (2017). Delivery of cytokines using gene electrotransfer. In D. MiklavÄiÄ (Ed.), Handbook of electroporation (pp. 1755-1768). Cham: Springer International Publishing. doi:10.1007/978-3-319-32886-7_189 Retrieved from https://doi.org/10.1007/978-3-319-32886-7_189

Showalter, A., Limaye, A., Oyer, J. L., Igarashi, R., Kittipatarin, C., Copik, A. J., & Khaled, A. R. (2017). Cytokines in immunogenic cell death: Applications for cancer immunotherapy. Cytokine, 97, 123-132. doi:S1043-4666(17)30153-9 [pii]

Simons, J. W., Mikhak, B., Chang, J. F., DeMarzo, A. M., Carducci, M. A., Lim, M., . . . Nelson, W. G. (1999). Induction of immunity to prostate cancer antigens: Results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Research, 59(20), 5160-5168.

Vacchelli, E., Aranda, F., Bloy, N., Buque, A., Cremer, I., Eggermont, A., . . . Galluzzi, L. (2015). Trial watch-immunostimulation with cytokines in cancer therapy. Oncoimmunology, 5(2), e1115942. doi:10.1080/2162402X.2015.1115942 [doi]

Verbik, D., & Joshi, S. (1995). Immune cells and cytokines - their role in cancer-immunotherapy (review). International Journal of Oncology, 7(2), 205-223.

Vonderheide, R. H., Aggarwal, C., Bajor, D. L., Goldenberg, J., Loch, C., Lee, J. C., . . . Bagarazzi, M. L. (2015). Study of hTERT and IL-12 DNA immunotherapy using electroporation in patients with solid tumors after definitive surgery and adjuvant therapy. Jco, 33(15), TPS3104-TPS3104. doi:10.1200/jco.2015.33.15_suppl.tps3104

Weinstein-Marom, H., Pato, A., Levin, N., Susid, K., Itzhaki, O., Besser, M. J., . . . Gross, G. (2016). Membrane-attached cytokines expressed by mRNA electroporation act as potent T-cell adjuvants. Journal of Immunotherapy (Hagerstown, Md.: 1997), 39(2), 60-70. doi:10.1097/CJI.0000000000000109 [doi]

Yarmush, M. L., Golberg, A., Sersa, G., Kotnik, T., & Miklavcic, D. (2014). Electroporation-based technologies for medicine: Principles, applications, and challenges. Annual Review of Biomedical Engineering, 16, 295-320. doi:10.1146/annurev-bioeng-071813-104622 [doi]