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

描述(由申请人提供)：我们研究计划的长期目标是开发对各种癌症有效的递送系统。这些研究的主要焦点是检查可用于免疫治疗方案的非病毒基因转移方法的使用及其作为实体瘤治疗的潜力。在体内，电穿孔作为一种增强包括肌肉、肿瘤、皮肤和肝脏在内的各种组织中的质粒DNA表达的手段，已经显示出巨大的前景。在此之前，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，几项研究表明，将编码细胞因子的质粒与电穿孔技术相结合，可以引发抗肿瘤反应。本申请中提出的具体研究旨在确定使用体内电穿孔传递编码细胞因子IL-15的质粒DNA是否可以有效治疗转移性黑色素瘤。本研究旨在实现以下特定目的：1.评价B16.F10黑色素瘤在电介导型IL-15载体介导下的生长或消退。二、检测IL-15电介导质粒导入后所诱发的肿瘤免疫应答和血清免疫应答。三、目的：评价IL-15基因在肿瘤内和肌肉内电介导对转移性黑色素瘤(包括皮下和肺内病变)生长的影响。四、目的：评价IL-15电介导质粒治疗黑色素瘤的潜在毒性。该项目的成功完成将展示IL-15基因治疗作为黑色素瘤治疗的潜在作用。 公共卫生相关性：通过给予免疫调节剂如细胞因子来刺激免疫系统以对抗黑色素瘤一直是许多研究的重点。不幸的是，这些治疗通常有毒副作用，因为所需剂量很高，而且在大多数情况下并不完全有效。一种降低这种治疗毒性的方法是用表达一个或多个这些分子的基因的质粒取代高剂量的重组蛋白注射，并直接注射到肿瘤中，或者注射到肿瘤周围的皮肤或肌肉中。这项研究将检验这一策略是否会通过利用编码IL-15的质粒直接进入肿瘤细胞而起作用。

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.