Murine Models of Genetic Immunotherapy with a p185HER2

描述(申请人提供)：HER2/neu癌基因在多种人类恶性疾病中过度表达，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p1 85HER2的抗体对乳腺肿瘤的生长具有抑制作用 过度表达受体，以及具有特异性的细胞溶解T细胞 HER2/neu衍生肽已被鉴定。这些发现表明， 设计转移性癌症免疫治疗干预措施的可能性 靶向抗体定义或T细胞定义的肿瘤的FIER2过表达 抗原表位。我们已经开发出嵌合T细胞受体(ChTCR)特异性 P185HER2。ChTCR包含AFP的抗原识别结构域(ScFv) 单抗，偶联于细胞内信号链 FcER或TCR。通过逆转录病毒基因导入原代T细胞 转移，嵌合受体引导MIHC不依赖，p1 85HER2特异性 T细胞反应，包括释放类Thi细胞因子和细胞因子 细胞毒性。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、组织穿透和 强大的靶细胞破坏免疫效应细胞。整体而言 这项拨款申请的目的是发展广泛的临床前 成功规划未来并获得监管部门批准所需的数据 使用chTCR进行遗传免疫治疗的临床试验。我们将广泛地 使用成熟的和特色化的动物模型来建立 这种新的癌症免疫治疗方法的治疗潜力。这个 这项建议的具体目的是：1)确定治疗效果 表达p185HER2基因修饰T细胞的过继免疫治疗 小鼠肿瘤模型中的特异性嵌合TCR；2)评价抗肿瘤作用 小鼠造血干细胞移植后的免疫反应 干细胞经过基因改造，表达p185HER2特异性嵌合TCR。

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.