ANCHOR MODIFIED PEPTIDES FOR IMMUNIZATION IN MELANOMA

用于黑色素瘤免疫的锚定修饰肽

• 批准号: 2825252
• 负责人: Gerald P Linette
• 金额: $ 13.47万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-29 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2825252
• 关键词: T lymphocyte; antigen antibody reaction; cellular immunity; clinical research; clinical trials; cytotoxic T lymphocyte; genetically modified animals; glycoproteins; human subject; human therapy evaluation; laboratory mouse; longitudinal human study; melanoma; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neoplastic process; peptides; protein binding; tumor antigens; vaccine development

Recent experimental evidence suggests that therapeutic immunization for certain malignancies is a realistic approach. Pre-clinical models based upon immunization of tumor-bearing hosts with antigen-pulsed dendritic cells (DC) demonstrate that regression of established tumors can be induced. Tumor regression is dependent upon an intact immune system and is mediated by antigen specific CD8+ T lymphocytes. This proposal is built upon the premise that delivery of an immunogenic peptide vaccine with subsequent intensive immunologic monitoring is required to optimally elicit an effective T cell response capable of eradicating residual tumor. Compelling evidence suggests that immunogenicity correlates with peptide binding affinity for molecules encoded by the major histocompatibility complex. The principal goal of this study is to create better, more immunogenic vaccines for melanoma by designing peptide antigens modified in crucial (anchor) residues that affect binding affinity for HLA class I molecules. Melanoma antigen gp100 and Mart-1 anchor modified peptides will be used with DC in clinical immunization trials designed to optimize the in vivo generation of antigen specific CD8+ cytotoxic T lymphocytes. Immunologic, pathologic, as well as radiologic endpoints will be used to judge the efficacy of each peptide. Newer methodologies such as T cell receptor beta chain repertoire analysis and four color flow cytometry will be incorporated into vaccine trials for melanoma to allow more precise monitoring. Immunogenicity of selected peptides will be validated using HLA transgenic mice. The specific aims of this application are: 1) to create anchor modified peptides of the gp100 melanoma antigen restricted by HLA-A2; 2) to identify HLA-B7 restricted epitopes of gp100 and Mart-1; 3) to develop better strategies to characterize human T cell activation and recruitment after DC vaccination. The issues addressed in this application are designed to provide a more detailed understanding of the relationship between cellular immunity, tumor regression, and clinical response.

最近的实验证据表明，对某些恶性肿瘤进行治疗性免疫是一种现实的方法。基于用抗原脉冲的树突状细胞（DC）对荷瘤宿主进行免疫的临床前模型表明，可以诱导已建立的肿瘤消退。 肿瘤消退依赖于完整的免疫系统，并由抗原特异性 CD8+ T 淋巴细胞介导。 该提议的前提是，需要提供免疫原性肽疫苗并随后进行强化免疫监测，以最佳地引发能够根除残留肿瘤的有效 T 细胞反应。 令人信服的证据表明，免疫原性与主要组织相容性复合物编码的分子的肽结合亲和力相关。 这项研究的主要目标是通过设计对影响 HLA I 类分子结合亲和力的关键（锚定）残基进行修饰的肽抗原，为黑色素瘤创造更好、更具免疫原性的疫苗。 黑色素瘤抗原 gp100 和 Mart-1 锚修饰肽将与 DC 一起用于临床免疫试验，旨在优化抗原特异性 CD8+ 细胞毒性 T 淋巴细胞的体内生成。 免疫学、病理学以及放射学终点将用于判断每种肽的功效。 T细胞受体β链谱分析和四色流式细胞术等更新的方法将被纳入黑色素瘤疫苗试验中，以实现更精确的监测。 所选肽的免疫原性将使用 HLA 转基因小鼠进行验证。 本申请的具体目的是：1）创建受HLA-A2限制的gp100黑色素瘤抗原的锚定修饰肽； 2) 鉴定gp100和Mart-1的HLA-B7限制性表位； 3) 制定更好的策略来表征 DC 疫苗接种后人类 T 细胞的激活和招募。 本申请中解决的问题旨在提供对细胞免疫、肿瘤消退和临床反应之间关系的更详细的理解。