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

描述：抗原快递已经开发了一种技术来强制演示 以产生有效的肿瘤细胞的方式产生内源性肿瘤抗原 疫苗。这一策略的关键是产生能够表达 缺少MHC II类相关不变量的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) 肿瘤。由于并不是所有的肿瘤都是MHC II类阳性，我们正在联合II类 IL-2和/或MHC-II类反式激活因子(CIITA)基因治疗的抑制作用。 IL-2的优势在于它能刺激抗原特异性T细胞的扩增 并导致干扰素-伽马的产生(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 利用小鼠肾细胞癌模型和Ang_2在体内的研究 卵巢腹水模型。对II的选择性抑制将使用 反向基因构建。最后，我们将确定其治疗效果。 联合IL-2(或CIITA)和II反向构建基因治疗的建立 活体Renca肿瘤和MOT腹水。成功将触发第二阶段研究， 其中我们将利用人类基因序列开发适当的结构， 在原发人类肿瘤样本中显示活性并完成所有必要的 IND申请所需的研究。 建议的商业应用： 免疫疗法代表了一种新的癌症治疗形式，与现有的 治疗方式。肿瘤免疫原性增强的成功论证 以一种产生强大的抗肿瘤免疫反应的方式将满足显著的 现代医疗保健中未得到满足的需求。

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.