COMBINED IL-2 AND MHC CLASS II GENE THERAPY FOR CANCER

IL-2 和 MHC II 类基因联合治疗癌症

• 批准号: 6292666
• 负责人: MINZHEN XU
• 金额: $ 28.74万
• 依托单位: ANTIGEN EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6292666
• 关键词: MHC class II antigen; antigen presentation; combination cancer therapy; gene therapy; immunocytochemistry; interleukin 2; invariant chain; kidney neoplasms; laboratory mouse; molecular cloning; neoplasm /cancer vaccine; ovary neoplasms; transfection /expression vector; tumor antigens; vaccine development; vector vaccine

DESCRIPTION: Antigen Express has developed technology to force the presentation of endogenous tumor antigens in a manner that produces an effective tumor cell vaccine. The key to this strategy is the generation of tumor cells that express MHC Class II molecules in the absence of the MHC Class II associated invariant chain (Ii protein). We are now developing an in vivo gene therapy strategy for inhibition of Ii protein expression (using Ii reverse gene constructs) in tumors. As not all tumors are MHC Class II positive, we are combining Ii inhibition with IL-2 and/or MHC Class II transactivator (CIITA) gene therapy. IL-2 is advantageous in that it stimulates the expansion of antigen specific T cells and causes interferon-gamma production (which is a good inducer of MHC Class II molecules) while CIITA is a potent and direct MHC Class II inducer. We will establish the ability of IL-2 and CIITA gene therapy vectors to induce MHC Class II molecules in vivo using a murine renal cell carcinoma model and an ovarian ascites model. Selective inhibition of Ii will be accomplished using a reverse gene construct. Finally, we will establish the therapeutic efficacy of combined IL-2 (or CIITA) and Ii reverse construct gene therapy on established Renca tumors and MOT ascites in vivo. Success will trigger Phase II studies, wherein we will develop appropriate constructs using human gene sequences, demonstrate activity in primary human tumor samples and complete all necessary studies requisite to an IND filing. PROPOSED COMMERCIAL APPLICATION: Immunotherapy represents a novel form of cancer therapy that complements existing treatment modalities. Successful demonstration of the augmentation of tumor immunogenicity in a manner that generates a robust anti-tumor immune response will satisify a significant unmet need in modern health care.

描述：Antigen Express开发了一种技术， 内源性肿瘤抗原的方式产生有效的肿瘤细胞 疫苗这一策略的关键是产生肿瘤细胞， 在不存在MHC II类相关恒定区的情况下的MHC II类分子 链（Ii蛋白）。我们现在正在开发一种体内基因治疗策略， 抑制Ii蛋白表达（使用Ii反向基因构建体） 肿瘤的由于并非所有肿瘤都是MHC II类阳性，我们将Ii 用IL-2和/或MHC II类反式激活因子（CIITA）基因疗法抑制。 IL-2是有利的，因为它刺激抗原特异性T细胞的扩增， 细胞并导致干扰素-γ产生（这是MHC的良好诱导剂 II类分子），而CIITA是一种有效和直接的MHC II类诱导剂。我们 将建立IL-2和CIITA基因治疗载体诱导MHC的能力 使用鼠肾细胞癌模型和免疫组织化学方法在体内检测II类分子。 卵巢腹水模型。Ii的选择性抑制将使用 反向基因构建体最后，我们将确定 联合IL-2（或CIITA）和Ii反向构建体基因疗法对已建立的 体内Renca肿瘤和MOT腹水。成功将启动第二阶段研究， 其中我们将使用人类基因序列开发适当的构建体， 在原发性人类肿瘤样品中证明活性，并完成所有必要的 研究是IND申请所必需的。 拟定商业应用： 免疫疗法代表了一种新的癌症治疗形式， 治疗方式。 成功证明肿瘤免疫原性增强 以产生强有力的抗肿瘤免疫应答的方式， 满足现代医疗保健的需求。