Abstract
Abstract Due to the limited success rate of conventional therapeutic approaches to soft tissue sarcomas, new treatment modalities, such as gene therapy, are being evaluated as adjuvant therapies to conventional methods. Electrogene therapy with interleukin-12 (IL-12) has been proved very effective due to the induction of adaptive immunity and innate resistance as well as anti-angiogenic action. The aim of our study was to evaluate the radiosensitizing effect of single and repetitive intratumoral (i.t.) mIL-12 electrogene therapy (mIL-12 EGT) in murine sarcoma. Solid SA-1 fibrosarcoma tumors were induced in the back of A/J mice by subcutaneous injection of tumor cells. The first therapeutic approach consisted of a single i.t. mIL-12 EGT (20 µg of plasmid DNA), followed by a single dose (10 Gy) or graded doses (2.5 – 70 Gy) of local tumor irradiation 24 h later. In the second therapeutic approach, tumor irradiation was followed by two additional i.t. mIL-12 EGT, on the third and fifth day. The tumor growth delay, complete response rates and local tumor control assay (TCD50 assay) were used as a measure of antitumor effectiveness of the therapies and skin damage in the irradiation field was also scored. Tumor and serum concentrations of cytokines mIL-12 and mouse interferon γ (mIFNγ) were measured using ELISA. Therapies with i.t. mIL-12 EGT demonstrated good antitumor effects in murine SA-1 sarcoma tumors and also a radiosensitizing effect when combined with irradiation. Both antitumor and radiosensitizing effects were more pronounced when using repetitive rather than single i.t. mIL-12 EGT. Single i.t. mIL-12 EGT resulted in 7% complete responses and, when combined with single dose irradiation, it produced a radiosensitizing effect resulting in 21% complete responses. In both cases we also detected significantly elevated levels of cytokines mIL-12 and mIFNγ in tumors but no significant increase of both cytokine levels in the serum. Repetitive i.t. mIL-12 EGT alone resulted in 75% complete responses and, when combined with single-dose irradiation, produced the most pronounced potentiation of the radiation response resulting in 100% complete responses of the treated tumors. The TCD50 value was 30 Gy for irradiation alone, and 13.8 Gy for i.t. mIL-12 EGT combined with irradiation. Therefore, the dose-modifying factor of a single i.t. mIL-12 EGT in murine SA-1 sarcoma was 2.17. At the same level of skin damage, dry desquamation, in combined therapy a 44% higher probability of local tumor control than with irradiation alone was observed. The results of our study demonstrate that i.t. mIL-12 EGT is an efficient treatment modality for treatment of soft tissue sarcoma alone and as adjuvant therapy to single dose irradiation. This is due to its pronounced radiosensitizing effect caused by boosting the immune response of the organism. The dose-modifying factor of a single i.t. mIL-12 EGT in murine SA-1 sarcoma was 2.17. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2669. doi:10.1158/1538-7445.AM2011-2669
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