Gregor Serša

Electrochemotherapy and gene therapy in cancer treatment

Elektrokemoterapija in genska terapija v zdravljenju raka

Prof. dr. Gregor Serša
Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia
Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia

Electrochemotherapy is an ablative treatment modality that has gained wide clinical acceptance in oncology. It utilizes the application of electric pulses to facilitate the uptake of cytotoxic drugs by tumor cells. The application of electric pulses is referred to as electroporation. Specific pulse parameters are used that reversibly permeabilize tumor cells and are not themselves cytotoxic to the cells. The cytotoxic drugs used are bleomycin or cisplatin, which are widely used in cancer therapy, but their transport through cell membranes is hampered. Therefore, electroporation facilitates the uptake of the drugs into the cells and significantly increases their cytotoxicity. Electrochemotherapy has proven its effectiveness in various skin tumors as well as in primary tumors and metastases of liver tumors, pancreatic tumors and also deep-seated sarcomas. The effectiveness is 60-80% response rate of the treated tumors and is comparable to other ablative techniques, both in the treatment of skin tumors and deep-seated tumors. However, the advantage of electrochemotherapy is that it is not a thermal ablation procedure, so it can be effectively and safely used also in tumors near larger blood vessels, as it is not subject to a heat sink effect. Cell death after electrochemotherapy is either necrotic, apoptotic, or immunogenic. Most importantly, the latter, immunogenic cell death, triggers a local immune response that contributes to the overall response of tumors treated with electrochemotherapy. This mechanism of action, i.e. immune response, is one of the three, the other two being enhanced drug delivery to tumor cells and vascular disrupting effects. Currently, the immunological effects of electrochemotherapy are being investigated depending on the tumor type and the drug used and its dosage to elicit the best immunological effects of electrochemotherapy. In this context, the current studies are aimed at enhancing the local immune response by adjuvant immunotherapy. The results of preclinical and also clinical studies suggest that electrochemotherapy indeed serves as an in-situ vaccine and can be enhanced by either immune checkpoint inhibitors or adjuvant cytokine stimulation. In this regard, gene therapy by gene transfer of plasmids encoding cytokines is one of the options. Therefore, we are currently investigating the safety and also the efficacy of gene electrotransfer of a plasmid encoding interleukin 12. Preclinical studies suggest a synergistic efficacy of the combined treatment and show that in this way the local efficacy of electrochemotherapy could be converted into a locoregional or even systemic treatment.

References

1. Clover AJP, deTerlizzi F, Bertino G, Curatolo P, Odili J, Campana LG, et al. Electrochemotherapy in the treatment of cutaneous malignancy: Outcomes and subgroup analysis from the cumulative results from the pan-European International Network for Sharing Practice in Electrochemotherapy gatabase for 2482 lesions in 987 patients (2008-2019). Eur J Cancer 2020; 138: 30-40. https://doi.org/10.1016/j.ejca.2020.06.020
2. Sersa G, Ursic K, Cemazar M, Heller R, Bosnjak M, Campana LG. Biological factors of the tumor response to electrochemotherapy: review of evidence and a research roadmap. EJSO 2021; 47: 1836-46.
3. Ursic K, Kos S, Kamensek U, Cemazar M, Miceska S, Markelc B, Bucek S, Staresinic B, Kloboves Prevodnik V, Heller R, Sersa G. Potentiation of electrochemotherapy effectiveness by immunostimulation with IL-12 gene electrotransfer in mice is dependent on tumor immune status. J Controlled Release 2021; 332: 623-35. https://doi.org/10.1016/j.jconrel.2021.03.009
4. Campana LG, Peric B, Mascherini M, Spina R, Kunte C, Kis E, Rozsa P, Quaglino P, Pritchard Jones R, Clover AJP, Curatolo P, Giorgione R, Cemazar M, de Terlizzi F, Bosnjak M, Sersa G. Combination of pembrolizumab with electrochemotherapy in cutaneous metastases from melanoma: A comparative retrospective study from the InspECT and Slovenian Cancer Registry. Cancers 2021; 13: 4289. doi: 10.3390/cancers13174289.

Gregor Serša

Gregor Serša graduated in 1978 from the Faculty of Biotechnology, University of Ljubljana, where he is currently Professor of Molecular Biology. He is employed at the Institute of Oncology Ljubljana at the Department of Experimental Oncology. He has devoted many years to translational research in experimental oncology. His particular area of interest is the influence of electric fields on tumor cells and tumors as a drug and gene delivery system in different therapeutic approaches. In addition to his experimental work, he is actively involved in the education of undergraduate and postgraduate students at the University of Ljubljana. Since 2015 he is member of Slovenian Academy of Science and Arts.