Combination cytokine gene therapy for melanoma treatment

对于可切除的高风险和转移性黑色素瘤患者，需要有效的全身治疗。虽然细胞因子治疗已显示出持久的缓解，但其使用一直受到低反应率和高相关毒性的阻碍。将研究两种可能提高反应率和增强治疗效果的策略。1)联合使用细胞因子比单独使用细胞因子能产生更强的、附加的或协同的抗肿瘤作用。使用组合方法，细胞因子组合将在小鼠模型中系统地测试黑色素瘤的治疗。将研究六种细胞因子：IFNa， TNFa, IL-2, GM-CSF， IL-12和IL-18。2)为了在肿瘤微环境中获得更大的细胞因子浓度，细胞因子基因将在瘤内传递。体内电穿孔是一种在许多组织中诱导一致、持久的高水平蛋白质表达的方法，将用于基因传递。将评估转导细胞因子的最佳表达条件。细胞因子组合将被系统筛选以诱导全身抗肿瘤活性。成功的组合将被测试对转移的排斥和诱导长期保护。在II期，将选择最佳组合进行进一步的表征和大型动物的临床前开发。拟议的商业应用：Ichor的电穿孔疗法（EPT）的初步研究表明，它可以提供一种将质粒DNA递送到肿瘤组织的有效手段。与其他非病毒的基因转移方法不同，EPT似乎能够可靠地实现高水平的基因表达。虽然这项技术有可能提供多种基于核苷酸的疗法。Ichor认为细胞因子基因的传递是进行初步研究的最合适的方法。EPT有潜力改善当前细胞因子治疗方法的治疗和毒理学特征。最初的适应症是转移性黑色素瘤患者，因为他们没有其他治疗方法。

Efficient systemic therapies are needed for the treatment of resectable high risk and metastatic melanoma patients. Although cytokine therapy has demonstrated durable remissions, its use has been hampered by low response rates and high associated toxicity. Two strategies that could potentially lead to increased response rate and enhanced therapeutic effect will be investigated. 1) Administering combinations of cytokines rather than single cytokines could result in stronger, additive or synergistic anti-tumor effects. Using a combinatorial approach, cytokine combinations will be systematically tested for treatment of melanoma in a murine model. Six cytokines will be studied: IFNa, TNFa, IL-2, GM-CSF, IL-12 and IL-18. 2) To obtain greater cytokine concentrations in the tumor microenvironment, cytokine genes will be delivered intratumorally. In vivo electroporation, a method that has proven to induce consistent, durable high level protein expression in a number of tissues, will be used for gene delivery. Conditions for the optimal expression of transduced cytokines will be assessed. Combinations of cytokines will be systematically screened for induction of systemic anti-tumor activity. Successful combinations will be tested for rejection of metastases and induction of long-term protection. Under Phase II, optimal combinations will be selected for further characterization and preclinical development in large animals. PROPOSED COMMERCIAL APPLICATIONS: Pilot studies of Ichor's Electroporation Therapy (EPT) suggest that it could provide an effective means of the delivery of plasmid DNA into tumor tissue. Unlike other non-viral methods of gene transfer, EPT appears to be capable of reliably achieving high levels of gene expression. While this technology could potentially delivery a variety of nucleotide based therapies. Ichor believes that the delivery of cytokine genes represents the most appropriate approach for initial investigation. EPT has the potential to improve the therapeutic and toxicological profile characteristic of current methods of cytokine therapy. Initial indications would metastatic melanoma patients, for whom there are for therapeutic alternatives.