Murine Models of Genetic Immunotherapy with a p185HER2

描述（由申请人提供）：HER 2/neu癌基因在人乳腺癌细胞中过表达。 多种人类恶性疾病，包括乳腺癌、卵巢癌、 癌症、结肠癌、胰腺癌和非小细胞肺癌。 针对p185 HER 2的抗体抑制乳腺肿瘤的生长 过表达受体的细胞，以及对 已经鉴定了HER 2/neu衍生肽。这些发现表明 为转移性癌症设计免疫干预措施的潜力 过表达靶向抗体确定的或T细胞确定的肿瘤的FIER 2 抗原表位。我们已经开发了嵌合T细胞受体（chTCR）特异性 p185HER2 chTCR含有免疫球蛋白的抗原识别结构域（scFv）。 单克隆抗体，偶联至源自 FcER或TCR。当通过逆转录病毒基因导入原代T细胞时 转移，嵌合受体指导MIHC独立，p1 85 HER 2特异性 T细胞应答，包括Th样细胞因子和细胞因子的释放 细胞毒因此，这种分子在基因上融合了精致的抗原 抗体分子的特异性与归巢，组织渗透，和 免疫效应细胞的有效靶细胞破坏。整体 这项拨款申请的目的是发展广泛的临床前 成功规划和获得监管批准所需的数据， chTCR基因免疫治疗的临床试验。我们将广泛 使用良好开发和表征的动物模型来建立 这种新的癌症免疫疗法的治疗潜力。的 本提案的具体目的是：1）确定 用表达p185 HER 2的遗传修饰的T细胞进行过继免疫治疗 小鼠肿瘤模型中的特异性嵌合TCR;和2）评估抗肿瘤作用 小鼠造血干细胞移植和植入后的反应 经遗传修饰以表达p185 HER 2特异性嵌合TCR的干细胞。

DESCRIPTION (provided by applicant): The HER2/neu oncogene is overexpressed in a variety of human malignant disorders, including breast cancer, ovarian cancer, colon cancer, pancreatic cancer, and non-small cell lung cancer. Antibodies directed to p1 85HER2 are inhibitory to the growth of breast tumors that overexpress the receptor, and cytolytic T-cells with specificity for HER2/neu derived peptides have been identified. These findings suggest the potential to devise immunotherapeutic interventions for metastatic cancer overexpressing FIER2 that target antibody defined or T-cell defined tumor antigen epitopes. We have developed chimeric T-cell receptors (chTCR) specific for p185HER2. The chTCR contains the antigen recognition domain (scFv) of a monoclonal antibody, coupled to an intracellular signaling chain derived from the FcER or TCR. When introduced into primary T-cells via retroviral gene transfer, the chimeric receptor directs MIHC independent, p1 85HER2 specific T-cell responses, including release of Thi-like cytokines and cellular cytotoxicity. Thus, this molecule genetically fuses the exquisite antigen specificity of an antibody molecule with the homing, tissue penetration, and potent target cell destruction of an immune effector cell. The overall objective of this grant application is to develop the extensive pre-clinical data necessary to successfully plan and receive regulatory approval for future clinical trials of genetic immunotherapy with the chTCR. We will make extensive use of well developed and characterized animal models to establish the therapeutic potential of this novel approach to cancer immunotherapy. The Specific Aims of this proposal are: 1) To define the therapeutic efficacy of adoptive immunotherapy with genetically modified T-cells expressing a p185HER2 specific chimeric TCR in murine tumor models; and 2) To evaluate anti-tumor responses following transplantation and engraftment of murine hematopoietic stem cells genetically modified to express a p185HER2 specific chimeric TCR.