Electroporation and Immunotherapy-Unleashing the Abscopal Effect

Abstract

The discovery of electroporation in 1968 has led to the development of electrochemotherapy (ECT) and irreversible electroporation (IRE). ECT and IRE have been established as treatments of cutaneous and subcutaneous tumors and locally advanced pancreatic cancer, respectively. Interestingly, the treatment modalities have been shown to elicit immunogenic cell death, which in turn can induce an immune response towards the tumor cells. With the dawn of the immunotherapy era, the potential of combining ECT and IRE with immunotherapy has led to the launch of numerous studies. Data from the first clinical trials are promising, and new combination regimes might change the way we treat tumors characterized by low immunogenicity and high levels of immunosuppression, such as melanoma and pancreatic cancer. In this review we will give an introduction to ECT and IRE and discuss the impact on the immune system. Additionally, we will present the results of clinical and preclinical trials, investigating the combination of electroporation modalities and immunotherapy.

Keywords: abscopal effect; electrochemotherapy; immune response; immunotherapy; irreversible electroporation.

Figure 1

(a) The strength and duration of electrical stimulation determines the cellular outcome. (b) The addition of agents such as chemotherapy can prevent cancer cells from recovery and lead to cell death. ECT, electrochemotherapy; IRE, irreversible electroporation. Created with BioRender.com (accessed on 7 April 2022).

Figure 2

The interplay between the peripheral immune system and the tumor microenvironment (TME). CAF, cancer-associated fibroblast; CCL, CC chemokine ligand; CTC, circulating tumor cell; IL, interleukin; MDSC, myeloid-derived suppressor cell; PD-L1, programmed death-ligand 1; TAM, tumor-associated macrophage; Treg, regulatory T cell; VEGF, vascular endothelial growth factor. Created with BioRender.com (accessed on 7 April 2022).

Figure 3

Model of how electroporation may induce an immune response and elicit an abscopal effect when combined with immunotherapy. aT cell, activated T cell; CAF, cancer-associated fibroblast; CTLA-4, cytotoxic T lymphocyte antigen 4; DAMP, damage-associated molecular pattern; DC, dendritic cell; ECT, electrochemotherapy; IRE, irreversible electroporation; NK cell, natural killer cell; PD-1, programmed death receptor 1; PD-L1, programmed death-ligand 1; TAA, tumor-associated antigen; TLR, Toll-like receptor; TLR3-L, TLR3 ligand; Treg, regulatory T cell. Created with BioRender.com (accessed on 7 April 2022).