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Electroporation in Oncology: Electrochemotherapy & Gene Electrotransfer

Electroporation in Oncology: Electrochemotherapy & Gene Electrotransfer

Reversible electroporation exploits a simple biophysical principle with profound therapeutic consequences: short, high-intensity electric pulses transiently destabilise the plasma membrane, creating a window of increased permeability. Molecules that would otherwise be excluded — cytotoxic drugs, plasmid DNA, siRNA/miRNA or mRNA — can then cross into the cytosol via different mechanisms. From this single principle, two clinically established modalities have emerged: electrochemotherapy (ECT) and more recently also gene electrotransfer (GET).

ECT, a local ablative therapy combines reversible electroporation with poorly permeant chemotherapeutics, most commonly bleomycin and cisplatin. By transiently opening the membrane, ECT amplifies the intracellular concentration and cytotoxicity of these agents by several orders of magnitude, confining the effect to the exposed tumor volume. Since the ESOPE project standardized operating procedures in the mid-2000s, ECT has become routine practice for cutaneous and subcutaneous tumors and metastases, with objective response rates frequently exceeding 80% and excellent local control. The technique’s reach has since expanded well beyond the skin: dedicated electrode configurations now enable treatment of deep-seated lesions in the liver, pancreas, bone (including vertebral metastases), and other visceral sites, extending ECT from a palliative dermatological tool toward a versatile local ablative therapy.

GET applies the same physical principle to deliver nucleic acids rather than drugs, offering a non-viral alternative for therapeutic gene delivery. In oncology, GET has been used mostly to express immunostimulatory molecules directly within the tumor microenvironment. Intratumoral GET of a plasmid encoding interleukin-12 (IL-12) is the most advanced example, promoting a local Th1-polarised response, activating cytotoxic effectors, and in favorable cases inducing regression of distant, untreated lesions — an abscopal-type systemic effect. First demonstrated in metastatic melanoma, the approach has since been extended to other tumor types and combined with immune checkpoint blockade to convert immunologically “cold” tumours into responsive ones. In Europe, the first clinical study of IL-12 GET was carried out in patients with basal cell carcinoma of the head and neck, using an antibiotic-resistance-gene-free phIL12 plasmid and confirming the safety and feasibility of the approach. Because GET avoids viral vectors, it circumvents concerns over insertional mutagenesis and anti-vector immunity, and allows repeated administration.

A recurring and increasingly important theme is that neither modality acts purely locally. Both ECT and GET can trigger immunogenic cell death, releasing damage-associated molecular patterns (DAMPs) and tumor antigens that prime adaptive immunity. This has motivated rational combinations — ECT paired with IL-12 GET, or with immune checkpoint inhibitors — designed to convert a local ablative effect into durable systemic anti-tumor immunity. The convergence of electroporation with immuno-oncology is one of the most active frontiers in the field.

A remaining challenge is equitable access: despite three decades of clinical evidence, electroporation-based treatments are still unevenly available across Europe and the rest of the world. In Europe, this is now being addressed within the EU4Health Joint Action JANE-2 (Joint Action on Networks of Expertise on Cancer), which is establishing Networks of Expertise — including one on high-technology medical resources — to position electrochemotherapy alongside other local ablative therapies and, in line with Europe’s Beating Cancer Plan, to bring these treatments within reach of the large majority (ideally at least 90%) of EU cancer patients.

— Contributed by Maja Čemažar

References

  1. Mir LM, Gehl J, Serša G, et al. Standard operating procedures of the electrochemotherapy: instructions for the use of bleomycin or cisplatin administered either systemically or locally and electric pulses delivered by the Cliniporator™ by means of invasive or non-invasive electrodes. Eur J Cancer Suppl. 2006;4(11):14–25. doi:10.1016/j.ejcsup.2006.08.003
  2. Marty M, Serša G, Garbay JR, et al. Electrochemotherapy — an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of the ESOPE study. Eur J Cancer Suppl. 2006;4(11):3–13. doi:10.1016/j.ejcsup.2006.08.002
  3. Serša G, Jarm T, Kotnik T, et al. Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer. 2008;98(2):388–398. doi:10.1038/sj.bjc.6604168
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  6. Gehl J, Serša G, Matthiessen LW, et al. Updated standard operating procedures for electrochemotherapy of cutaneous tumours and skin metastases. Acta Oncol. 2018;57(7):874–882. doi:10.1080/0284186X.2018.1454602
  7. Algazi A, Bhatia S, Agarwala S, et al. Intratumoral delivery of tavokinogene telseplasmid yields systemic immune responses in metastatic melanoma patients. Ann Oncol. 2020;31(4):532–540. doi:10.1016/j.annonc.2019.12.008
  8. Algazi AP, Twitty CG, Tsai KK, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. Clin Cancer Res. 2020;26(12):2827–2837. doi:10.1158/1078-0432.CCR-19-2217
  9. Strojan P, Jesenko T, Omerzel M, et al. Phase I trial of phIL12 plasmid intratumoral gene electrotransfer in patients with basal cell carcinoma in the head and neck region. Eur J Surg Oncol. 2025;51:109574. doi:10.1016/j.ejso.2025.109574
  10. Joint Action on Networks of Expertise on Cancer (JANE-2), EU4Health Programme, Grant Agreement No. 101183265. https://jane-2.eu

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