Abstract #4641: The antitumor effectiveness of intramuscular mIL-12 gene therapy and local tumor irradiation of murine sarcoma tumors
Authors: Gregor Sersa, Gregor Tevz, Andrej Coer, Simona Kranjc, Suzana Vidic, Urska Kamensek, Mojca Krzan, Maja Cemazar
Journal: Cancer Research (2009)

Antitumor efficacy of intramuscular  mIL-12  gene electrotransfer (EGT) in solid subcutaneous sarcoma tumors and their induced lung metastases, alone or combined with local tumor or lung irradiation was studied, and possible interaction between the treatment approaches evaluated. Lung metastases and subcutaneous tumors were induced by intravenous or subcutaneous injection of SA-1 or LPB tumor cells, respectively. Electrotransfer of mIL-12 was performed by intramuscular injection of plasmid DNA followed by local application of electric pulses. Mice bearing subcutaneous tumors were treated by  mIL-12  EGT 3-times every second day. Tumor irradiation was performed 1 day after the first EGT. Treatment effectiveness was evaluated by tumor growth delay assay. Mice with induced lung metastases were treated by EGT 24 h before (prophylactic treatment) or at three different time points after the injection of cancer cells. Tumor irradiation was performed 3 days after first EGT. Eight or 14 days post-treatment, mice were sacrificed and the number of metastases determined. In addition, total mIL-12 and IFN-\#947; in serum were determined by ELISA. Histological changes were also examined. Intramuscular  mIL-12  EGT resulted in significant antitumor effect in solid tumors, observed by prolonged tumor growth delay, and 13 - 28% complete responses of the tumors (LPB and SA-1 tumors respectively). Even higher percentage of complete responses was observed in combined EGT and local tumor irradiation (100% in LPB and 44% in SA-1 tumors). A pronounced effect of intramuscular  mIL-12  EGT was observed also in induced lung metastases. Up to 80% reduction in lung metastases was observed by EGT alone, if performed before the injection of cancer cells, as prophylactic treatment. Combination of EGT with irradiation of lung metastases resulted in 98% reduction of lung metastases. Serum IL-12 and IFN-\#947; were profoundly increased after EGT, up to 200-fold compared to baseline levels. The achieved peak concentrations of both IL-12 and IFN-\#947; were higher in C57BL/6 (LPB host mouse model) than in A/J (SA-1 host mouse model). Immune cells were infiltrated into the transfected muscle tissue and muscle fiber necrosis was observed after intramuscular EGT. Extensive muscle regeneration was already visible 1 week after electrotransfection and by the end of the observation period of 28 days, almost no infiltration of immune cells and many regenerated muscle fibers were observed. The study demonstrates that intramuscular gene therapy with IL-12 has good antitumor effect in distantly located subcutaneous sarcoma tumors, and has prophylactic antimetastatic effect. The effect is mediated by sustained release of IL-12 and IFN-\#947; in the bloodstream. Furthermore, gene therapy has synergistic antitumor effect combined with local tumor irradiation.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4641.