Electroporation-Based Cancer Treatment. Selected Papers from the 4th World Congress on Electroporation

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (28 April 2023) | Viewed by 18344

Special Issue Editor

1. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
2. Center for Experimental Drug and Gene Electrotransfer (C*EDGE), Department of Clinical Oncology and Palliative Care, Zealand University Hospital, Sygehusvej 10, 4000 Roskilde, Denmark
Interests: Cancer; Oncology; Electroporation; Electrochemotherapy; Calcium electroporation; Exercise Oncology

Special Issue Information

Dear Colleagues,

Electric fields can cause cell permeabilization (electroporation), and this is increasingly being used in cancer therapy. Cell permeabilization may be transient (reversible), allowing for the passage of molecules, e.g.: chemotherapy (electrochemotherapy); ions; nucleotides, such as DNA; RNA. With higher field strengths, irreversible electroporation (IRE) can be achieved, leading to cancer cell death through the loss of cell integrity. The field is developing with different types of electric pulses as well as novel equipment, expanding indications.

This Special Issue brings together papers on basic and clinical research from presentations at the 4th world congress on Electroporation, held in Copenhagen in 2021. Electroporation based cancer therapy is being used for the treatment of cancer of different histologies and for tumors located, for example, in the skin, head and neck area, gastrointestinal tract, as well as in tumors in the liver. Basic research is developing our understanding of underlying mechanisms and expanding indications for treatment. This Special Issue bridges basic and clinical research in electroporation based cancer therapy, highlighting the developmental frontier within the field.

Prof. Dr. Julie Gehl
Guest Editor

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Keywords

  • electroporation
  • cancer
  • electrochemotherapy
  • calcium electroporation
  • irreversible electroporation (IRE)

Published Papers (9 papers)

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Research

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22 pages, 6405 KiB  
Article
The Effect of Partial Electrical Insulation of the Tip and Active Needle Length of Monopolar Irreversible Electroporation Electrodes on the Electric Field Line Pattern and Temperature Gradient to Improve Treatment Control
Cancers 2023, 15(17), 4280; https://doi.org/10.3390/cancers15174280 - 26 Aug 2023
Viewed by 541
Abstract
Unintentional local temperature effects can occur during irreversible electroporation (IRE) treatment, especially near the electrodes, and most frequently near the tip. Partial electrical insulation of the IRE electrodes could possibly control these temperature effects. This study investigated and visualized the effect of partial [...] Read more.
Unintentional local temperature effects can occur during irreversible electroporation (IRE) treatment, especially near the electrodes, and most frequently near the tip. Partial electrical insulation of the IRE electrodes could possibly control these temperature effects. This study investigated and visualized the effect of partial electrical insulation applied to the IRE electrodes on the electric field line pattern and temperature gradient. Six designs of (partial) electrical insulation of the electrode tip and/or active needle length (ANL) of the original monopolar 19G IRE electrodes were investigated. A semolina in castor oil model was used to visualize the electric field line pattern in a high-voltage static electric field. An optical method to visualize a change in temperature gradient (color Schlieren) was used to image the temperature development in a polyacrylamide gel. Computational models were used to support the experimental findings. Around the electrode tip, the highest electric field line density and temperature gradient were present. The more insulation was applied to the electrodes, the higher the resistance. Tip and ANL insulation together reduced the active area of and around the electrodes, resulting in a visually enlarged area that showed a change in temperature gradient. Electrically insulating the electrode tip together with an adjustment in IRE parameter settings could potentially reduce the uncontrollable influence of the tip and may improve the predictability of the current pathway development. Full article
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14 pages, 1388 KiB  
Article
High-Frequency Electroporation and Chemotherapy for the Treatment of Cutaneous Malignancies: Evaluation of Early Clinical Response
Cancers 2023, 15(12), 3212; https://doi.org/10.3390/cancers15123212 - 16 Jun 2023
Cited by 1 | Viewed by 823
Abstract
High-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local [...] Read more.
High-frequency electroporation (HF-EP) with chemotherapy is a novel therapy proposed for both curative and palliative treatment of cutaneous malignancies. The use of high-frequency biphasic pulses is thought to reduce the painful muscle contractions associated with traditional electrochemotherapy (ECT), allowing treatment administration under local anaesthesia. This proof-of-concept study investigated the efficacy and tolerability of HF-EP protocols on a variety of cutaneous malignancies. A total of 97 lesions of five different histological subtypes were treated across 25 patients. At 12 weeks post-treatment, a 91.3% overall lesion response rate was observed (complete response: 79%; partial response: 12.3%), with excellent intraprocedural patient tolerability under local anaesthetic. HF-EP with chemotherapy shows promising results regarding tumour response rates for cutaneous malignancies of varying histological subtypes when compared to traditional ECT protocols. Improved patient tolerability is important, increasing the possibility of treatment delivery under local anaesthesia and potentially broadening the treatment envelope for patients with cutaneous malignancies. Full article
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12 pages, 3307 KiB  
Article
Efficacy of Electrochemotherapy in Breast Cancer Patients of Different Receptor Status: The INSPECT Experience
Cancers 2023, 15(12), 3116; https://doi.org/10.3390/cancers15123116 - 08 Jun 2023
Cited by 1 | Viewed by 1764
Abstract
Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple [...] Read more.
Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ (p = 0.0297) and HR+ (p = 0.0094), while overall survival was affected by time to local progression in all groups (p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions. Full article
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12 pages, 9628 KiB  
Article
Safety and Feasibility of Vulvar Cancer Treatment with Electrochemotherapy
Cancers 2023, 15(12), 3079; https://doi.org/10.3390/cancers15123079 - 07 Jun 2023
Viewed by 5884
Abstract
Electrochemotherapy is a local ablative therapy used for the treatment of various superficial and deep-seated tumors. Electrochemotherapy involves the application of electric pulses locally to tumors to destabilize cell membranes and facilitate the entry of cytotoxic drugs, thereby enhancing their cytotoxicity locally. The [...] Read more.
Electrochemotherapy is a local ablative therapy used for the treatment of various superficial and deep-seated tumors. Electrochemotherapy involves the application of electric pulses locally to tumors to destabilize cell membranes and facilitate the entry of cytotoxic drugs, thereby enhancing their cytotoxicity locally. The aim of our study is to investigate the safety and feasibility of electrochemotherapy in patients with vulvar cancer recurrence used for nonpalliative purposes. Ten patients with single local vulvar cancer recurrence were treated with intravenous bleomycin, followed by a local application of electric pulses (electrochemotherapy) to the tumor. Adverse events were determined using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The feasibility of treating vulvar cancer with electrochemotherapy was determined by an appropriate selection of electrodes based on the size and location of the tumor with safety margins included. Electrochemotherapy was feasible in all patients. No electrochemotherapy-related or other serious adverse events occurred. Our data suggest that electrochemotherapy is a feasible and safe technique for the treatment of vulvar cancer recurrence for nonpalliative purposes. Based on our results, electrochemotherapy might be a viable therapeutic tool for patients who would otherwise undergo surgery involving a mutilation of the external genitalia. Full article
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12 pages, 1308 KiB  
Article
Qualitative Investigation of Experience and Quality of Life in Patients Treated with Calcium Electroporation for Cutaneous Metastases
Cancers 2023, 15(3), 599; https://doi.org/10.3390/cancers15030599 - 18 Jan 2023
Cited by 5 | Viewed by 1138
Abstract
(1) Background: Calcium electroporation is a novel cancer treatment. It includes injecting calcium-solution and applying electric pulses to tumour tissue. Data on quality of life for patients with cutaneous metastases treated with calcium electroporation is limited. We evaluated quality of life in patients [...] Read more.
(1) Background: Calcium electroporation is a novel cancer treatment. It includes injecting calcium-solution and applying electric pulses to tumour tissue. Data on quality of life for patients with cutaneous metastases treated with calcium electroporation is limited. We evaluated quality of life in patients with skin metastases treated with calcium electroporation using qualitative interviews. (2) Methods: This investigation featured a subgroup from a non-randomised phase II study (CaEP-R) at Zealand University Hospital, Denmark, studying response to calcium electroporation in cutaneous metastasis (ClinicalTrials no. NCT04225767). Participants were interviewed at baseline before calcium electroporation treatment and after two months. Data was analysed phenomenologically; (3) Results: Interviews were conducted February 2020–November 2021. Nine patients were included, of which seven participated in both interviews. All seven patients expected treated tumours to disappear, symptom relief and minimal side effects. Most patients requested peer accounts. All patients found the treatment uncomfortable but acceptable; all thought their fears of electric pulses exceeded their experience. All would repeat the treatment if effective. Successful treatment had a positive effect on pain, symptomatic wounds, sleep, vigour and social inclination; (4) Conclusions: Calcium electroporation enhanced health-related quality of life by reducing symptoms and increasing social inclination. Peer accounts provide patients with a shortcut to confidence in treatment on top of doctors’ recommendations. Full article
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26 pages, 5704 KiB  
Article
High-Frequency Nanosecond Bleomycin Electrochemotherapy and its Effects on Changes in the Immune System and Survival
Cancers 2022, 14(24), 6254; https://doi.org/10.3390/cancers14246254 - 19 Dec 2022
Cited by 5 | Viewed by 1446
Abstract
In this work, a time-dependent and time-independent study on bleomycin-based high-frequency nsECT (3.5 kV/cm × 200 pulses) for the elimination of LLC1 tumours in C57BL/6J mice is performed. We show the efficiency of nsECT (200 ns and 700 ns delivered at 1 kHz [...] Read more.
In this work, a time-dependent and time-independent study on bleomycin-based high-frequency nsECT (3.5 kV/cm × 200 pulses) for the elimination of LLC1 tumours in C57BL/6J mice is performed. We show the efficiency of nsECT (200 ns and 700 ns delivered at 1 kHz and 1 MHz) for the elimination of tumours in mice and increase of their survival. The dynamics of the immunomodulatory effects were observed after electrochemotherapy by investigating immune cell populations and antitumour antibodies at different timepoints after the treatment. ECT treatment resulted in an increased percentage of CD4+ T, splenic memory B and tumour-associated dendritic cell subsets. Moreover, increased levels of antitumour IgG antibodies after ECT treatment were detected. Based on the time-dependent study results, nsECT treatment upregulated PD 1 expression on splenic CD4+ Tr1 cells, increased the expansion of splenic CD8+ T, CD4+CD8+ T, plasma cells and the proportion of tumour-associated pro inflammatory macrophages. The Lin population of immune cells that was increased in the spleens and tumour after nsECT was identified. It was shown that nsECT prolonged survival of the treated mice and induced significant changes in the immune system, which shows a promising alliance of nanosecond electrochemotherapy and immunotherapy. Full article
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12 pages, 1853 KiB  
Article
Palliative Treatment of Esophageal Cancer Using Calcium Electroporation
Cancers 2022, 14(21), 5283; https://doi.org/10.3390/cancers14215283 - 27 Oct 2022
Cited by 6 | Viewed by 1566
Abstract
Calcium electroporation (CaEP) is a novel cancer therapy wherein high intracellular calcium levels, facilitated by reversible electroporation, trigger tumor necrosis. This study aimed to establish safety with CaEP within esophageal cancer. Patients with non-curable esophageal cancer were included at Copenhagen University Hospital Rigshospitalet [...] Read more.
Calcium electroporation (CaEP) is a novel cancer therapy wherein high intracellular calcium levels, facilitated by reversible electroporation, trigger tumor necrosis. This study aimed to establish safety with CaEP within esophageal cancer. Patients with non-curable esophageal cancer were included at Copenhagen University Hospital Rigshospitalet in 2021 and 2022. In an outpatient setting, calcium gluconate was injected intratumorally followed by reversible electroporation applied with an endoscopic electrode. The primary endpoint was the prevalence of adverse events, followed by palliation of dysphagia. All patients were evaluated with CT and upper endoscopies up to two months after treatment. The trial was registered at ClinicalTrials.gov (NCT04958044). Eight patients were treated. One serious adverse event (anemia, requiring a single blood transfusion) and three adverse events (mild retrosternal pain (two) and oral thrush (one)) were registered. Initially, six patients suffered from dysphagia: two reported dysphagia relief and four reported no change. From the imaging evaluation, one patient had a partial response, three patients had no response, and four patients had progression. Six months after treatment, the patient who responded well was still in good condition and without the need for further oncological treatment. CaEP was conducted in eight patients with only a few side effects. This study opens the way for larger studies evaluating tumor regression and symptom palliation. Full article
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17 pages, 3375 KiB  
Article
Induction of Bystander and Abscopal Effects after Electroporation-Based Treatments
Cancers 2022, 14(15), 3770; https://doi.org/10.3390/cancers14153770 - 02 Aug 2022
Cited by 2 | Viewed by 1664
Abstract
Electroporation-based antitumor therapies, including bleomycin electrotransfer, calcium electroporation, and irreversible electroporation, are very effective on directly treated tumors, but have no or low effect on distal nodules. In this study, we aimed to investigate the abscopal effect following calcium electroporation and bleomycin electrotransfer [...] Read more.
Electroporation-based antitumor therapies, including bleomycin electrotransfer, calcium electroporation, and irreversible electroporation, are very effective on directly treated tumors, but have no or low effect on distal nodules. In this study, we aimed to investigate the abscopal effect following calcium electroporation and bleomycin electrotransfer and to find out the effect of the increase of IL-2 serum concentration by muscle transfection. The bystander effect was analyzed in in vitro studies on 4T1tumor cells, while abscopal effect was investigated in an in vivo setting using Balb/c mice bearing 4T1 tumors. ELISA was used to monitor IL-2 serum concentration. We showed that, similarly to cell treatment with bleomycin electrotransfer, the bystander effect occurs also following calcium electroporation and that these effects can be combined. Combination of these treatments also resulted in the enhancement of the abscopal effect in vivo. Since these treatments resulted in an increase of IL-2 serum concentration only in mice bearing one but not two tumors, we increased IL-2 serum concentration by muscle transfection. Although this did not enhance the abscopal effect of combined tumor treatment using calcium electroporation and bleomycin electrotransfer, boosting of IL-2 serum concentration had a significant inhibitory effect on directly treated tumors. Full article
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Review

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42 pages, 2998 KiB  
Review
Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation
Cancers 2023, 15(13), 3340; https://doi.org/10.3390/cancers15133340 - 25 Jun 2023
Cited by 4 | Viewed by 1562
Abstract
The 4th World Congress of Electroporation (Copenhagen, 9–13 October 2022) provided a unique opportunity to convene leading experts in pulsed electric fields (PEF). PEF-based therapies harness electric fields to produce therapeutically useful effects on cancers and represent a valuable option for a variety [...] Read more.
The 4th World Congress of Electroporation (Copenhagen, 9–13 October 2022) provided a unique opportunity to convene leading experts in pulsed electric fields (PEF). PEF-based therapies harness electric fields to produce therapeutically useful effects on cancers and represent a valuable option for a variety of patients. As such, irreversible electroporation (IRE), gene electrotransfer (GET), electrochemotherapy (ECT), calcium electroporation (Ca-EP), and tumour-treating fields (TTF) are on the rise. Still, their full therapeutic potential remains underappreciated, and the field faces fragmentation, as shown by parallel maturation and differences in the stages of development and regulatory approval worldwide. This narrative review provides a glimpse of PEF-based techniques, including key mechanisms, clinical indications, and advances in therapy; finally, it offers insights into current research directions. By highlighting a common ground, the authors aim to break silos, strengthen cross-functional collaboration, and pave the way to novel possibilities for intervention. Intriguingly, beyond their peculiar mechanism of action, PEF-based therapies share technical interconnections and multifaceted biological effects (e.g., vascular, immunological) worth exploiting in combinatorial strategies. Full article
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