Skip to main content
SpringerLink
Log in
Book cover

Handbook of Electroporation pp 1–15Cite as

Combined Treatment of Electrochemotherapy with Immunomodulators

  • Living reference work entry
  • First Online:

Abstract

Electrochemotherapy is a nonthermal tumor ablation modality. The local delivery of electric pulses directly to the tumor transiently increases permeabilization of the cell membrane and significantly increases the uptake of chemotherapeutic drugs into cells. Several mechanisms, including active immune response, contribute to the antitumor effectiveness of electrochemotherapy. After electrochemotherapy, the tumor-associated antigens are released in situ; however, they are not presented to the cells of the immune system efficiently to stimulate also a distant antitumor response. Although electrochemotherapy alone can stimulate the immune system, the induced immune response is not sufficient to also obtain a systemic effect. Combining electrochemotherapy with adjuvant immunomodulatory molecules is a promising approach to stimulate the immune system more effectively and thus increase antitumor effectiveness of electrochemotherapy. This approach has been evaluated in preclinical studies on experimental and spontaneous tumor models. Electrochemotherapy can be combined with different immunomodulatory molecules, including cytokines, such as interleukin-2 and interleukin-12, CpG oligodeoxynucleotides, monoclonal antibodies, and plasmids coding immunomodulatory molecules. Results of the preclinical studies combining electrochemotherapy with immunomodulatory molecules are promising. In addition to potentiation of local antitumor effectiveness, a systemic response can be obtained which affects also distant untreated tumors, namely, reducing the number of metastasis and cures of untreated tumors. The induced antitumor response is tumor specific, generating tumor-specific cytotoxic T cells and protection against the development of the same tumor type. Based on these results, combination of electrochemotherapy and immunomodulatory molecules bears a great potential for cancer therapy, specifically by adding a systemic component to localized electrochemotherapy treatment.

This is a preview of subscription content, log in via an institution.

References

  • Andersen MH, Gehl J, Reker S et al (2003) Dynamic changes of specific T cell responses to melanoma correlate with IL-2 administration. Semin Cancer Biol 13:449–459. doi:10.1016/j.semcancer.2003.09.009

    Article  Google Scholar 

  • Brizio M, Fava P, Astrua C et al (2015) Complete regression of melanoma skin metastases after electrochemotherapy plus ipilimumab treatment: an unusual clinical presentation. Eur J Dermatol 25:271–272. doi:10.1684/ejd.2015.2522

    Google Scholar 

  • Cemazar M, Todorovic V, Scancar J et al (2015) Adjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness. Radiol Oncol 49:32–40. doi:10.1515/raon-2015-0005

    Google Scholar 

  • 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 1–14. doi: 10.1111/vco.12208

    Google Scholar 

  • Cutrera J, King G, Jones P et al (2015) Safe and effective treatment of spontaneous neoplasms with interleukin 12 electro-chemo-gene therapy. J Cell Mol Med 19:664–675. doi:10.1111/jcmm.12382

    Article  Google Scholar 

  • Cutrera J, Torrero M, 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. doi:10.1007/978-1-59745-194-9_24

    Article  Google Scholar 

  • Gehl J, Skovsgaard T, Mir LM (1998) Enhancement of cytotoxicity by electropermeabilization: an improved method for screening drugs. Anticancer Drugs 9:319–325. doi:10.1097/00001813-199804000-00005

    Article  Google Scholar 

  • Gerlini G, Sestini S, Di Gennaro P et al (2013) Dendritic cells recruitment in melanoma metastasis treated by electrochemotherapy. Clin Exp Metastasis 30:37–45. doi:10.1007/s10585-012-9505-1

    Article  Google Scholar 

  • Heller L, Pottinger C, Jaroszeski MJ et al (2000) In vivo electroporation of plasmids encoding GM-CSF or interleukin-2 into existing B16 melanomas combined with electrochemotherapy induces long-term antitumour immunity. Melanoma Res 10:577–583. doi:10.1097/00008390-200012000-00010

    Article  Google Scholar 

  • Hribernik A, Cemazar M, Sersa G et al (2016) Effectiveness of electrochemotherapy after IFN-α adjuvant therapy of melanoma patients. Radiol Oncol 50:21–27. doi:10.1515/raon-2015-0048

    Google Scholar 

  • Jaroszeski MJ, Dang V, Pottinger C et al (2000) Toxicity of anticancer agents mediated by electroporation in vitro. Anticancer Drugs 11:201–208. doi:10.1097/00001813-200003000-00008

    Article  Google Scholar 

  • Mali B, Miklavcic D, Campana LG et al (2013) Tumor size and effectiveness of electrochemotherapy. Radiol Oncol 47:32–41. doi:10.2478/raon-2013-0002

    Article  Google Scholar 

  • Mekid H, Tounekti O, Spatz A et al (2003) In vivo evolution of tumour cells after the generation of double-strand DNA breaks. Br J Cancer 88:1763–1771. doi:10.1038/sj.bjc.6600959

    Article  Google Scholar 

  • Miklavcic D, Mali B, Kos B et al (2014) Electrochemotherapy: from the drawing board into medical practice. Biomed Eng Online 13:29. doi:10.1186/1475-925X-13-29

    Article  Google Scholar 

  • Mir LM, Roth C, Orlowski S et al (1995) Systemic antitumor effects of electrochemotherapy combined with histoincompatible cells secreting interleukin-2. J Immunother 17:30–38

    Article  Google Scholar 

  • Mozzillo N, Simeone E, Benedetto L et al (2015) Assessing a novel immuno-oncology-based combination therapy: Ipilimumab plus electrochemotherapy. Oncoimmunology 4:e1008842. doi:10.1080/2162402X.2015.1008842

    Article  Google Scholar 

  • Orlowski S, Belehradek J, Paoletti C, Mir LM (1988) Transient electropermeabilization of cells in culture. Increase of the cytotoxicity of anticancer drugs. Biochem Pharmacol 37:4727–4733. doi:10.1016/0006-2952(88)90344-9

    Article  Google Scholar 

  • 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. doi:10.4161/cbt.8.22.9734

    Article  Google Scholar 

  • Pavlin D, Cemazar M, Coer A et al (2011) Electrogene therapy with interleukin-12 in canine mast cell tumors. Radiol Oncol 45:30–39. doi:10.2478/v10019-010-0041-9

    Article  Google Scholar 

  • Ramirez LH, Orlowski S, An D et al (1998) Electrochemotherapy on liver tumours in rabbits. Br J Cancer 77:2104–2111

    Article  Google Scholar 

  • Reed SD, Fulmer A, Buckholz J et al (2010) Bleomycin/interleukin-12 electrochemogene therapy for treating naturally occurring spontaneous neoplasms in dogs. Cancer Gene Ther 17:457–464. doi:10.1126/scisignal.2001449.Engineering

    Article  Google Scholar 

  • Roux S, Bernat C, Al-Sakere B et al (2008) Tumor destruction using electrochemotherapy followed by CpG oligodeoxynucleotide injection induces distant tumor responses. Cancer Immunol Immunother 57:1291–1300. doi:10.1007/s00262-008-0462-0

    Article  Google Scholar 

  • Schreiber RD, Old LJ, Smyth MJ (2011) Cancer Immunoediting: Integrating Immunity’s Roles in Cancer Suppression and Promotion. Science 331:1565–1570. doi:10.1126/science.1203486

    Article  Google Scholar 

  • 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. doi:10.2478/v10019-012-0044-9

    Article  Google Scholar 

  • Sersa G, Cemazar M, Miklavcic D (1995) Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice. Cancer Res 55:3450–3455

    Google Scholar 

  • Sersa G, Cemazar M, Menart V et al (1997) Antitumor effectiveness of electrochemotherapy is increased by TNF-a on SA-1 tumors in mice. Cancer Lett 116:85–92

    Article  Google Scholar 

  • 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. doi:10.1002/jgm

    Article  Google Scholar 

  • Torrero MN, Henk WG, Li S (2006) Regression of high-grade malignancy in mice by bleomycin and interleukin-12 electrochemogenetherapy. Clin Cancer Res 12:257–263. doi:10.1158/1078-0432.CCR-05-1514

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska 2, SI-1000, Ljubljana, Slovenia

    Vesna Todorovic & Maja Cemazar

  2. Faculty of Health Sciences, University of Primorska, Polje 42, SI-6310, Izola, Slovenia

    Maja Cemazar

Authors
  1. Vesna Todorovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maja Cemazar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vesna Todorovic or Maja Cemazar .

Editor information

Editors and Affiliations

  1. Faculty of Electrical Enginer, University of Ljubljana, Ljubljana, Slovenia

    Damijan Miklavcic

Section Editor information

  1. Frank Reidy Research Center for Bioelectrics, Old Dominion University, 4211 Monarch Way, Suite 300, VA 23508, Norfolk, Virginia, USA

    Richard Heller

  2. Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloškacesta 2, SI-1000, Ljubljana, Slovenia

    Gregor Serša

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing AG

About this entry

Cite this entry

Todorovic, V., Cemazar, M. (2016). Combined Treatment of Electrochemotherapy with Immunomodulators. In: Miklavcic, D. (eds) Handbook of Electroporation. Springer, Cham. https://doi.org/10.1007/978-3-319-26779-1_62-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-26779-1_62-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Online ISBN: 978-3-319-26779-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Societies and partnerships

Search

Navigation