TARGETED THERAPEUTIC VACCINATION IN PROSTATE CANCER

描述：(申请人摘要)本次修订的总体思路 应用的是开发一种靶向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 依赖于RNA的端粒DNA合成。在过去的一年里，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。 主要目的是证明人类端粒酶的多肽是 免疫原性1)前列腺癌患者淋巴细胞的体外免疫原性，以及2) 转人HLA-A2.1分子的小鼠体内和携带A细胞的小鼠体内试验 前列腺癌模型。这些目标将通过四个目标来实现。(1) 人类白细胞抗原A2.1限制性人(H)TRT多肽的鉴定和检测。(2) 重组hTRT多肽体外免疫原性的优化 自然或人工信号序列和靶点突变以增加 MHC结合的亲和力。(3)前列腺癌患者CTL的诱导。 申请者将评估暴露于癌症是否会改变 可用的外周血库(例如，通过耐受性或克隆无能)和 降低hTRT多肽的前体频率和它们的能力 在免疫后进行扩增。申请者将学习人类白细胞抗原-A2.1+ 有前列腺癌临床/组织学诊断的个人。及(4)在 用两种转基因小鼠模型研究端粒酶多肽的体内免疫原性， 一个是人类人类白细胞抗原-A2.1分子，另一个是猿猴病毒(SV)40 大T抗原，其中SV40标签与前列腺癌有关。使用 第一个转基因模型，他将测试hTRT多肽诱导 HLA-A2.1-限制CTL反应。使用第二个转基因模型，并使用 小鼠的TRT多肽，他将回答这个问题：前列腺的存在 肿瘤会影响对端粒酶多肽的免疫吗？

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?"