Cyclin B-1 As a Tumor-specific Antigen in Oral Carcinoma

Cyclin B-1 作为口腔癌中的肿瘤特异性抗原

• 批准号: 6541368
• 负责人: Olivera J Finn
• 金额: $ 12.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541368
• 关键词: cyclins; cytotoxic T lymphocyte; helper T lymphocyte; human subject; immunomodulators; laboratory mouse; mouth neoplasms; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; nonhuman therapy evaluation; patient oriented research; recombinant proteins; squamous cell carcinoma; tumor antigens; vaccine development

DESCRIPTION: (provided by applicant) For active specific immunotherapy to become a reality, tumor specific antigens must be identified. A new antigen discovery system was used based on in vitro grown human dendritic cells presenting peptides purified by HPLC from class I molecules of human tumors to healthy naive CD8+ and CD4+ T cells. They identified several immunostimulatory peptides and determined they were derived from cycling B1 protein. They also found cyclin B1 specific T cells in patients with head and neck cancer whose tumors overexpressed this protein. Further studies showed that cyclin B1 is overexpressed in a large number of human tumors, including those of the head and neck, and that this overexpression is a result of in activation of p53 function. Based on these results, they hypothesize that cyclin B1 may be a good target of an immune response in oral cancer and that cyclin B1 protein and peptides derived from it would be good candidates for oral cancer vaccines. They propose to test this hypothesis by conducting in vitro and pre-clinical studies in vivo in mouse models. In specific aim 1, they will use recombinant cyclin B1 protein to evaluate its potential to elicit not only CTL responses but also helper T cell responses. In vitro priming will be employed using dendrite cells loaded with the whole protein or individual peptides to generate T cells specific for this antigen and to identify as large a repertoire as possible of cyclin B1 peptides stimulatory to both CD8+ and CD4+ cells. In specific aim 2, they will test the potential of cyclin B1 to be a tumor rejection antigen in vivo. They will utilize the p53 knockout mouse as a model of cancer prevention and cancer therapy of spontaneous tumors though vaccination with cyclin B1. They will also employ a transplantable tumor model of a mouse squamous cell carcinoma that grows in the oral cavity.

描述：（由申请人提供） 为了使主动特异性免疫疗法成为现实，肿瘤特异性抗原 必须被识别。采用基于体外的新抗原发现系统 生长的人树突状细胞呈递通过 HPLC 纯化的 I 类肽 人类肿瘤分子转化为健康的初始 CD8+ 和 CD4+ T 细胞。他们 鉴定了几种免疫刺激肽并确定它们是衍生的 来自循环 B1 蛋白。他们还在患者体内发现了细胞周期蛋白 B1 特异性 T 细胞 头颈癌患者的肿瘤过度表达这种蛋白质。更远 研究表明cyclin B1在大量人类细胞中过度表达 肿瘤，包括头部和颈部的肿瘤，并且这种过度表达是 p53 功能激活的结果。根据这些结果，他们 假设细胞周期蛋白 B1 可能是口服免疫反应的良好靶标 癌症，细胞周期蛋白 B1 蛋白和源自它的肽会很好 口腔癌疫苗的候选者。他们建议通过以下方式检验这一假设 在小鼠模型中进行体外和体内临床前研究。 在具体目标1中，他们将使用重组cyclin B1蛋白来评估其 不仅有可能引发 CTL 反应，还可能引发辅助 T 细胞反应。在 将使用负载整个细胞的树突细胞进行体外引发 蛋白质或单个肽以产生对该抗原具有特异性的 T 细胞 并鉴定尽可能大的细胞周期蛋白 B1 肽库 对 CD8+ 和 CD4+ 细胞都有刺激作用。在具体目标 2 中，他们将测试 细胞周期蛋白B1作为体内肿瘤排斥抗原的潜力。他们会 利用p53基因敲除小鼠作为癌症预防和癌症模型 通过接种细胞周期蛋白 B1 来治疗自发性肿瘤。他们还将 采用小鼠鳞状细胞癌的可移植肿瘤模型 生长在口腔内。