RAS-SPECIFIC T-CELL MEDIATED IMMUNOTHERAPY

RAS 特异性 T 细胞介导的免疫治疗

• 批准号: 2096041
• 负责人: Martin Alexander Cheever
• 金额: $ 25.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2096041
• 关键词: CD4 molecule; CD8 molecule; T lymphocyte; cell mediated cytotoxicity; cellular immunity; chemical carcinogen; chemical carcinogenesis; dendritic cells; disease /disorder model; gene expression; gene mutation; helper T lymphocyte; immunogenetics; laboratory mouse; model design /development; neoplasm /cancer immunotherapy; nucleic acid sequence; oncogenes; oncoproteins; protein structure; protooncogene; synthetic peptide

DESCRIPTION (Adapted from the applicant's abstract): Ras proto-oncogenes encode a highly conserved family of 21kD proteins collectively designated as p21. In animals, carcinogens induce very specific and predictable nucleotide substitutions in ras genomic DNA, usually at or near codons 12 or 61. The resultant single amino acid substitutions in the primary protein structure alter the tertiary structure and impart transforming activity. In humans, a substantial proportion of malignancies of a variety of histologic types are associated with activating mutations in the same codons of ras. In preliminary studies the applicant has demonstrated that specific T cell immunity to mutated ras p21 protein can be elicited by immunization with synthetic peptides constructed to be identical to the mutated portion of the ras protein. Thus, the protein products of mutated ras proto-oncogenes represent potential tumor-specific antigens both related to the oncogenic event and "shared" by many tumors. The goal of the proposed studies is to develop in murine models the principles and methodologies for generating and for utilizing ras-specific T cell immunity in cancer therapy. The specific aims of this application are: (1) To develop methods of generating CD4+ helper/inducer T cells immune to mutated ras protein. (2) To develop methods for generating CD8+ T cells specifically cytolytic to tumor cells expressing mutated ras proteins. (3) To determine the therapeutic potential of ras-specific T cells against transplanted tumors in adoptive therapy models. (4) To examine the diagnostic and therapeutic potential of ras-specific immunity in hosts bearing primary carcinogen-induced malignancies. (5) To develop the use of primary in vitro immunization with dendritic antigen presenting cells as a means for generating ras-specific T cells and for determining which ras peptides and proteins are recognized by host T cells.

描述（改编自申请人的摘要）：RAS原始基因 编码一个高度保守的21kD蛋白质家族 作为p21。 在动物中，致癌物诱导非常具体和可预测的 RAS基因组DNA中的核苷酸取代，通常在密码子或附近12 或61。产生的单一氨基酸取代 蛋白质结构改变了三级结构并赋予转化 活动。 在人类中，各种各样的恶性肿瘤很大一部分 组织学类型与同一激活突变有关 Ras的密码子。 在初步研究中，申请人表明 特异性T细胞对突变的Ras P21蛋白的免疫可以通过 与构建的合成肽免疫相同 RAS蛋白的突变部分。 因此，突变的蛋白质产物 Ras原始基因代表潜在的肿瘤特异性抗原 与许多肿瘤的致癌事件和“共享”有关。 目标 拟议的研究是在鼠模型中发展原理和 生成和利用RAS特异性T细胞免疫的方法学 在癌症治疗中。 此应用程序的具体目的是：（1） 开发生成CD4+辅助/诱导剂T细胞免疫的方法 RAS蛋白。 （2）开发生成CD8+ T细胞的方法 特别是表达突变Ras蛋白的肿瘤细胞的细胞溶解。 （3） 确定RAS特异性T细胞的治疗潜力 收养治疗模型中的移植肿瘤。 （4）检查 RAS特异性免疫的诊断和治疗潜力 轴承原发性致癌物引起的恶性肿瘤。 （5）开发使用 用树突状抗原呈现细胞作为A的一级体外免疫作为A 用于生成RAS特异性T细胞并确定哪些RAS的方法 肽和蛋白质被宿主T细胞识别。