Abstract B25: The effect of peritumoral gene electrotransfer of interleukin-12 as an adjuvant immunotherapy to electrochemotherapy varies according to immune status of treated tumors
Authors: Ursic Katja , Kos Spela , Kamensek Urska , Cemazar Maja , Sersa Gregor 
Published: March 2020

Abstract
The aim of the study was to test a new combined therapy including electrochemotherapy (ECT) and gene electrotransfer (GET) of plasmid encoding interleukin-12 (IL-12) in three immunologically different tumors. Therapeutic effectiveness of ECT in the clinics is up to 80% of local tumor control. However, systemic antitumor effect (abscopal effect) has not been observed. We proposed a combined therapy consisting of ECT with intratumoral application of cisplatin, oxaliplatin, or bleomycin with peritumoral GET of plasmid encoding IL-12. In the combination, IL-12 boosts the in situ vaccination effect of ECT and together with immunogenic cell death and danger-associated molecular patterns release recruits effector immune cells. Our hypothesis was that IL-12 potentiates the effect of ECT on a local and systemic level and may vary regarding immunologic profile of the treated tumors. The therapy was tested in three immunologically different primary murine tumor models (malignant melanoma [B16F10], mammary carcinoma [4T1], and colon carcinoma [CT26]) and on dual-flank melanoma model mimicking systemic disease. Tumor growth was followed and blood samples were collected for immunohistochemical and cytometric analysis of the tumor microenvironment and for the detection of IL-12. We demonstrated that GET of IL-12 potentiates the effect of ECT with all three chemotherapeutic drugs on local level. The most pronounced potentiation was with ECT using cisplatin, resulting in 38% of complete responses as well as an abscopal effect. The antitumor effectiveness of this treatment combination could be ascribed to the induction of the local and systemic immune response. Furthermore, the combined therapy was also tested in two other immunologically different tumor models, 4T1 and CT26. The results indicate that peritumoral GET of IL-12 inversely correlates with tumor response to ECT. We observed better responsiveness to ECT in more immunogenic tumors, where the addition of GET led to the lowest potentiation. So far, we have demonstrated an abscopal effect after the combination of ECT with cisplatin and peritumoral IL-12 GET in B16F10 tumor model. Currently, we are also testing the systemic effect of the combined therapy in 4T1 and CT26 tumor models. In conclusion, we showed that peritumoral GET of IL-12 significantly potentiates ECT in treated melanoma tumors and has notable effect on distant untreated tumors, predominantly when cisplatin was used for ECT. Potentiation of this treatment combination depends on the immunologic status of the tumors. ECT was more effective in more immunogenic tumors, but the contribution of peritumoral GET was not as pronounced as in less immunogenic tumors.
Citation Format: Katja Ursic, Spela Kos, Urska Kamensek, Maja Cemazar, Gregor Sersa. The effect of peritumoral gene electrotransfer of interleukin-12 as an adjuvant immunotherapy to electrochemotherapy varies according to immune status of treated tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B25.