New era of electrochemotherapy in treatment of liver tumors in conjunction with immunotherapies

Abstract

Electrochemotherapy is a local ablative therapy that increases the cytotoxicity of either bleomycin or cisplatin by applying electric pulses (electroporation) to tumors. It has already been widely used throughout Europe for the treatment of various types of human and veterinary cutaneous tumors, with an objective response rate ranging from 70%-90%, depending on the tumor histotype. Recently, electrochemotherapy was introduced for the treatment of primary liver tumors, such as hepatocellular carcinoma (HCC). The complete response rate was 85% per treated lesion, with a durable response. Therefore, electrochemotherapy could become a treatment of choice for HCC, especially after achieving a transition from an open surgery approach to a percutaneous approach that uses dedicated electrodes. Electrochemotherapy elicits a local immune response and can be considered an in situ vaccination. HCC, among others, is a potentially immunogenic tumor; thus, electrochemotherapy could boost adjuvant immunotherapy to achieve a better and longer-lasting antitumor response. Therefore, therapeutic strategies that combine electrochemotherapy with immune checkpoint inhibitors or adjuvant treatment with cytokines are indicated for HCC. Immunogene therapy using electroporation as a delivery system for plasmid DNA coding for interleukin-12 is a highly promising approach. This electroporation approach has shown efficacy in preclinical settings and veterinary oncology and is awaiting translation for the treatment of liver tumors, i.e., HCC.

Keywords: Electroporation; Electrochemotherapy; Gene therapy; Gene electrotransfer; Interleukin-12; Immune checkpoint inhibitors; Hepatocellular carcinoma

Core Tip: Electrochemotherapy was found to be feasible, safe and highly effective for the treatment of hepatocellular carcinoma (HCC). A local immune response is induced through the destruction of tumor cells; therefore, the electrochemotherapy approach can be considered an in situ vaccination. Electrochemotherapy combined with immune checkpoint inhibitors had an interactive effect on melanoma tumors and HCC. Furthermore, electrochemotherapy can be combined with immunostimulation with cytokines. Electrochemotherapy involving the gene electrotransfer of a plasmid DNA coding for interleukin-12 (IL-12) has already been shown to have clinical value. The combination of electrochemotherapy and immunogene therapy with IL-12 via electroporation might be a feasible new treatment strategy for HCC that is also potentially applicable to other liver tumors.