CANCER VACCINATION AGAINST TELOMERASE

针对端粒酶的癌症疫苗

• 批准号: 6628502
• 负责人: Eli Gilboa
• 金额: $ 24.26万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628502
• 关键词: CD40 molecule; actin binding protein; active immunization; bladder neoplasm; breast neoplasms; carcinoembryonal antigen; cytotoxic T lymphocyte; dendritic cells; embryo /fetus antigen; gene targeting; genetically modified animals; helper T lymphocyte; interleukin 2; laboratory mouse; melanoma; metastasis; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; oligonucleotides; prostate neoplasms; telomerase; transfection; tumor antigens; vaccine development

DESCRIPTION: (Applicant's Abstract) Vaccination with antigens that are expressed in a broad spectrum of histologically distinct unrelated tumor cell types would be highly desirable. The polypeptide component of telomerase, also know as telomerase reverse transcriptase or TERT, is an attractive candidate for a broadly expressed tumor antigen since telomerase is silent in normal tissues but is reactivated in over 85% of cancers. The primary objective of this application is to test the hypothesis that telomerase can function as a broadly useful tumor rejection antigen, namely that vaccination against telomerase can generate protective immunity against a wide range of unrelated tumors. The proposed studies will be carried out using murine tumor models. The specific aims of this application are: 1) to determine whether vaccination against murine telomerase using dendritic cells transfected with telomerase RNA will induce CTL and engender protective immunity against histologically distinct tumors of unrelated origin, 2) to explore the hypothesis and the mechanism underlying the immunosubdominant nature of telomerase as antigen (see Preliminary Data section), 3) to explore strategies to augment the antitumor response elicited by vaccination with telomerase RNA transfected DC. Here the applicant will test the hypothesis that stimulating a telomerase-specific CD4 T cell response, T-help, is necessary for generating an optimal anti-telomerase CTL and anti-tumor immune response and will explore combination therapies to enhance the anti-telomerase and anti-tumor response generated by vaccination with telomerase RNA transfected DC. 4) The last specific aim is to evaluate two additional candidates for broadly expressed tumor rejection antigens: Oncofetal antigen (OFA) and filamin-1. The long term objective of this project is to identify several broadly expressed tumor antigens, which in combination will provide an effective and widely applicable treatment to cancer patients. The studies proposed in this application will provide the foundations for this ambitious goal.

描述：（申请人摘要）使用以下抗原进行疫苗接种： 在广泛的组织学上不同的无关肿瘤细胞中表达 类型将是非常理想的。端粒酶的多肽成分， 称为端粒酶逆转录酶或 TERT，是一个有吸引力的候选者 对于广泛表达的肿瘤抗原，因为端粒酶在正常细胞中是沉默的 但在超过 85% 的癌症中会重新激活。主要目标 这个应用程序是为了测试端粒酶可以作为端粒酶发挥作用的假设 广泛使用的肿瘤排斥抗原，即疫苗接种 端粒酶可以产生针对多种不相关物质的保护性免疫力 肿瘤。拟议的研究将使用小鼠肿瘤模型进行。这 该应用程序的具体目的是： 1) 确定是否接种疫苗 使用转染端粒酶 RNA 的树突状细胞对抗鼠端粒酶 将诱导 CTL 并产生针对组织学的保护性免疫 不同起源的不同肿瘤，2）探索假设和 端粒酶作为抗原的免疫亚显性本质的机制（参见 初步数据部分），3）探索增强抗肿瘤的策略 接种端粒酶 RNA 转染的 DC 引起的反应。这里的 申请人将测试刺激端粒酶特异性 CD4 T 的假设 细胞反应（T-help）对于产生最佳的抗端粒酶是必要的 CTL和抗肿瘤免疫反应，并将探索联合疗法 增强疫苗接种产生的抗端粒酶和抗肿瘤反应 用端粒酶RNA转染DC。 4）最后一个具体目标是评估两个 广泛表达的肿瘤排斥抗原的其他候选者：Oncofetal 抗原 (OFA) 和 filamin-1。该项目的长期目标是 鉴定几种广泛表达的肿瘤抗原，将其结合起来 为癌症患者提供有效且广泛适用的治疗方法。这 本申请中提出的研究将为这一点提供基础 雄心勃勃的目标。