Extracellular Targeted Heat Shock Protein Tumor Vaccine

细胞外靶向热休克蛋白肿瘤疫苗

• 批准号: 6727646
• 负责人: Zihai Li
• 金额: $ 13.56万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-23 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727646
• 关键词: T lymphocyte; breast neoplasms; dendritic cells; gene expression; genetically modified animals; glycoproteins; heat shock proteins; immunocytochemistry; interferon gamma; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; protooncogene

DESCRIPTION: (provided by Applicant) Heat shock proteins (HSP) are gaining increasing attention in immunology because of their two critical functions: (1) their ability to chaperone and present antigenic peptides to specific T cells; (2) their emerging roles in activating antigen presenting cells. It has been shown that the constitutive secretion of an endogenous HSP gp96 leads to potent immunogenicity of tumors. Since surface expression and secretion of gp96 have been observed in a variety of cell types, this application hypothesizes that the surface expression and secretion of gp96-peptide complexes precedes cell death as the first mode of antigen release into the tumor microenvironment, which is therefore important in the priming of tumor- specific T cells. The specific objectives are: (1) To determine if tumor cells with gp96 targeted extracellularly are more immunogenic in solid tumor model; (2) To study the differences of mechanisms of immunity elicited by wild type tumor cells, with surface-expressing tumor cells and tumors that secrete gp96 constitutively; (3) To perform a pre-clinical study of immunotherapy of spontaneous breast cancer in a Her-2/neu transgenic mouse model with breast cancer cells engineered to express gp96 extracellularly; (4) To initiate a pilot phase I study for the treatment of patients with Her-2/neu expressing cancer using tumor cells that secrete gp96 constitutively. The applicant's interests are in the early events in priming tumor-specific T cells. Ultimately, he hopes to develop immunologically based cancer treatment strategies, thus combining his training in both immunology and medical oncology. After 5 year clinical training, he now returns to the field he started, and to his Ph.D. mentor, Pramod K. Srivastava, who pioneered the field of HSP in immunity, and is committed to the full independence of the applicant.

描述：（由申请人提供）热休克蛋白（HSP）正在增加 由于其两个关键功能，免疫学日益受到关注： (1) 它们陪伴和将抗原肽呈递给特定 T 的能力 细胞； (2)它们在激活抗原呈递细胞中的新作用。 它 已表明内源性 HSP gp96 的组成型分泌导致 肿瘤的强免疫原性。 由于表面表达和分泌 gp96 已在多种细胞类型中观察到，本应用 假设 gp96 肽的表面表达和分泌 复合物在细胞死亡之前作为抗原释放到细胞中的第一种模式 肿瘤微环境，因此对于肿瘤的启动非常重要 特异性T细胞。 具体目标是：（1）确定肿瘤是否 细胞外靶向 gp96 的细胞在实体瘤中更具免疫原性 模型; (2) 研究野生动物免疫机制的差异 型肿瘤细胞，具有表面表达的肿瘤细胞和分泌肿瘤细胞的肿瘤 gp96组成型； （3）开展免疫治疗的临床前研究 Her-2/neu 转基因小鼠乳腺模型中的自发性乳腺癌 癌细胞被改造为在细胞外表达 gp96； (4) 发起 用于治疗 Her-2/neu 表达患者的试验性 I 期研究 使用持续分泌 gp96 的肿瘤细胞来治疗癌症。 申请人的兴趣在于启动肿瘤特异性 T 的早期事件 细胞。 最终，他希望开发基于免疫学的癌症治疗方法 策略，从而将他在免疫学和医学方面的训练结合起来 肿瘤学。 经过5年的临床训练，他现在回到了自己的领域 开始，并获得博士学位。 导师 Pramod K. Srivastava，他是 免疫领域的 HSP 领域，并致力于完全独立 申请人。