Combined Treatment of electrochemotherapy with immunomodulators

Abstract

Electrochemotherapy is a nonthermal tumor ablation modality. The local delivery of electric pulses directly to the tumor transiently increases permeabilization of the cell membrane and significantly increases the uptake of chemotherapeutic drugs into cells. Several mechanisms, including active immune response, contribute to the antitumor effectiveness of electrochemotherapy. After electrochemotherapy, the tumor-associated antigens are released in situ; however, they are not presented to the cells of the immune system efficiently to stimulate also a distant antitumor response. Although electrochemotherapy alone can stimulate the immune system, the induced immune response is not sufficient to also obtain a systemic effect. Combining electrochemotherapy with adjuvant immunomodulatory molecules is a promising approach to stimulate the immune system more effectively and thus increase antitumor effectiveness of electrochemotherapy. This approach has been evaluated in preclinical studies on experimental and spontaneous tumor models. Electrochemotherapy can be combined with different immunomodulatory molecules, including cytokines, such as interleukin-2 and interleukin-12, CpG oligodeoxynucleotides, monoclonal antibodies, and plasmids coding immunomodulatory molecules. Results of the preclinical studies combining electrochemotherapy with immunomodulatory molecules are promising. In addition to potentiation of local antitumor effectiveness, a systemic response can be obtained which affects also distant untreated tumors, namely, reducing the number of metastasis and cures of untreated tumors. The induced antitumor response is tumor specific, generating tumor-specific cytotoxic T cells and protection against the development of the same tumor type. Based on these results, combination of electrochemotherapy and immunomodulatory molecules bears a great potential for cancer therapy, specifically by adding a systemic component to localized electrochemotherapy treatment.