Therapeutic Potential of IL-15 Plasmid Delivery to Tumors Using Electroporation

描述（由申请人提供）：我们研究项目的长期目标是开发对各种癌症有效的给药系统。这些研究的主要重点是检查非病毒基因转移方法的使用，该方法可用于免疫治疗方案及其作为实体瘤治疗的潜力。体内电穿孔作为一种增强质粒DNA在多种组织（包括肌肉、肿瘤、皮肤和肝脏）中的表达的手段，已经显示出很大的前景。此前，在临床前和临床研究中，体内电穿孔已被证明是提高化疗药物有效性的有效方法。最近，一些研究表明，将编码细胞因子的质粒与电穿孔结合可以引起抗肿瘤反应。本申请中提出的具体研究旨在确定使用体内电穿孔传递细胞因子IL-15编码的质粒DNA是否可有效治疗转移性黑色素瘤。该研究将被设计来完成以下具体目标：1 .评估B16。电介导IL-15质粒递送对F10黑色素瘤生长或消退的影响2。测定电介导IL-15质粒递送后引起的肿瘤和血清免疫反应。3。评估肿瘤内和肌肉内电介导的IL-15质粒递送对转移性黑色素瘤生长的影响，包括皮下和肺部病变。iv.评估电介导的IL-15质粒递送治疗黑色素瘤的潜在毒性。该项目的成功完成将证明IL-15基因疗法作为电穿孔质粒作为黑色素瘤治疗的潜在作用。

DESCRIPTION (provided by applicant): The long range goal of our research program is the development of delivery systems that will be effective for a variety of cancers. The major focus of these studies is to examine the use of non-viral gene transfer approach that can be used for immunotherapy protocols and its potential as a treatment of solid tumors. In vivo electroporation has shown a great deal of promise as a means of enhancing the expression of plasmid DNA in a variety of tissues including muscle, tumor, skin and liver. Previously, in vivo electroporation has been shown to be an effective way to enhance the effectiveness of chemotherapeutic agents in both pre-clinical and clinical studies. More recently, several studies have shown that delivering a plasmid coding for a cytokine in combination with electroporation can elicit an anti-tumor response. The specific research proposed in this application is intended to determine if the using in vivo electroporation to deliver a plasmid DNA coding for the cytokine IL-15 can be effective in treating metastatic melanoma. The study will be designed to accomplish the following specific aims: i. to evaluate B16.F10 melanoma growth or regression in response to electrically mediated IL-15 plasmid delivery. ii. To determine tumor and serum immune responses elicited after electrically mediated IL-15 plasmid delivery. iii. To evaluate the effect of intratumoral and intramuscular electrically mediated IL-15 plasmid delivery on the growth of metastatic melanomas, including both subcutaneous and lung lesions. iv. To evaluate the potential toxicity of electrically mediated IL-15 plasmid delivery for the treatment of melanoma. Successful completion of this project will demonstrate the potential role of IL-15 gene therapy delivered as a plasmid by electroporation as a therapy for melanoma. Public Health Relevance: The stimulation of the immune system through the administration of immunomodulatory agents such as cytokines to fight melanoma has been the focus of a number of studies. Unfortunately, these treatments usually have toxic side effects because of the high doses required and in most cases have not been completely effective. A method to decrease the toxicity of this type of treatment is to replace the high dose recombinant protein injections with plasmids expressing genes for one or more of these molecules and injecting either directly into the tumor or to the skin around the tumor or into the muscle. This study will examine if this strategy will work by utilizing a plasmid coding for IL-15 delivered directly into tumor cells.