TARGETED THERAPEUTIC VACCINATION IN PROSTATE CANCER

描述：（申请人的摘要）本修改的实施例的总体思想是： 应用是开发一种针对逆转的前列腺癌疫苗 端粒酶转录酶（TRT），一种独特的核糖核蛋白，介导 端粒DNA的RNA依赖性合成。在过去一年中，申请人 已经获得了令人信服的证据，证明这一想法是有效的，值得追求。 主要目标是证明人端粒酶的肽是 免疫原性：1）对前列腺癌患者淋巴细胞的体外免疫原性，和2） 在人HLA-A2.1分子的转基因小鼠和携带人HLA-A2.1分子的小鼠中， 前列腺癌模型这些目标将在四个方面实现。（一） 鉴定和测试HLA-A2.1限制性人（h）TRT肽。（二） 具有以下的融合（hTRT）肽的体外肽免疫原性的优化 天然或人工信号序列和靶向点突变， MHC结合的亲合力。(3)在前列腺癌患者中诱导CTL， 其中申请人将评估暴露于癌症是否会改变 可用的外围设备库（例如，通过耐受性或克隆无反应性）和 降低了hTRT肽的前体频率和它们 在免疫接种后进行扩张。申请人将研究HLA-A2.1+ 临床/组织学诊断为前列腺癌的个体。（4）在 使用两种转基因小鼠模型的端粒酶肽的体内免疫原性， 一个针对人HLA-A2.1分子，另一个针对猿猴病毒（SV）40 大T抗原，其中SV 40标签负责前列腺癌。使用 第一个转基因模型，他将测试hTRT肽诱导 HLA-A2.1限制性CTL应答。使用第二转基因模型，并使用 鼠TRT肽，他将回答问题“是否存在前列腺 肿瘤影响端粒酶肽免疫？"

DESCRIPTION: (Applicant's Abstract) The general idea of this revised application is to develop a prostate cancer vaccine targeted to the reverse transcriptase of telomerase (TRT), a unique ribonucleoprotein that mediates RNA-dependent synthesis of telomeric DNA. During the past year, the applicant has obtained compelling evidence that this idea is valid and worth pursuing. The main goals are to demonstrate that peptides of human telomerase are immunogenic 1) in vitro for lymphocytes of prostate cancer patients, and 2) in vivo in mice transgenic for the human HLA-A2.1 molecule and in mice bearing a model prostate cancer. These objectives will be pursued in four aims. (1) Identification and testing HLA-A2.1 restricted human (h)TRT peptides. (2) Optimization of peptide immunogenicity in vitro of fusion (hTRT) peptides with natural or artificial signal sequences and targeted point mutations to increase the avidity of MHC binding. (3) Induction of CTL in prostate cancer patients, in which the applicant will assess whether exposure to cancer modifies the available peripheral repertoire (e.g., by tolerance or clonal anergy) and diminishes the precursor frequency for hTRT peptides and their ability to undergo expansion upon immunization. The applicant will study HLA-A2.1+ individuals with clinical/histological diagnosis of prostate cancer. And (4) In vivo immunogenicity of telomerase peptides using two transgenic mouse models, one for the human HLA-A2.1 molecule and the other for the simian virus (SV) 40 large T antigen where SV40 Tag is responsible for prostate cancer. Using the first transgenic model he will test the ability of hTRT peptides to induce HLA-A2.1-restricted CTL responses. Using the second transgenic model, and using murine TRT peptides, he will answer the question "Does presence of prostate tumor affect immunization against telomerase peptides?"