IMMUNITY TO HER-2/NEU PROTEIN IN BREAST CANCER

乳腺癌中对 HER-2/NEU 蛋白的免疫力

基本信息

批准号：
3205144
负责人：
Martin Alexander Cheever
金额：
$ 21.58万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 1996-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3205144
关键词：
antitumor antibody breast neoplasm /cancer diagnosis breast neoplasms cytotoxic T lymphocyte helper T lymphocyte human subject leukocyte activation /transformation neoplasm /cancer immunology neoplasm /cancer immunotherapy oncoproteins prognosis tissue /cell culture

项目摘要

The HER-2/neu proto-oncogene is amplified and overexpressed in 20-40% of invasive breast cancers. HER-2/neu overexpression is associated with aggressive disease and is an independent predictor of poor prognosis in several subsets of patients. HER-2/neu may also be related to cancer formation, with overexpression being detectable in 50-60% of ductal carcinomas in situ. The overall goal for our laboratory has been to develop specific T cell therapy directed against proteins involved in malignant transformation. We have begun to examine immunity to HER-2/neu protein in breast cancer patients. Our preliminary studies have discovered that some patients with breast cancer have existent CD4+ helper/inducer T cell immunity and antibody-mediated immunity to HER-2/neu protein. It has been assumed that normal individuals would be immunologically tolerant to overexpressed oncogenic proteins and that immunity could not be generated; however, if immunity could be generated, the result would be destructive autoimmunity. Preliminary data demonstrating that HER-2/neu-reactive T cells and antibody are already present in the peripheral blood of breast cancer patients implies that immunity to HER-2/neu is induced in some individuals with cancer by virtue of the presence of growing tumor expressing the antigen and gives credence to the concept that HER-2/neu- specific immunity can be used in therapy without destroying normal tissue. Detection of immunity to HER-2/neu might also provide a method for screening and early detection of breast cancer and changes in the level of immunity might correlate with disease state an predict relapses. Additional preliminary studies demonstrated that primary in vitro immunization with HER-2/neu peptide fragments can by used to elicit HER- 2/neu peptide-specific CD8+ cytotoxic T cells (CTL). Methods to elicit HER-2/neu peptide-specific CD8+ T cells should provide a means to determine whether patients with breast cancer have existent CTL responses to HER- 2/neu and may provide a means of generating CTL capable of lysing autologous cancer cells for eventual use in therapy. The overall goal of this proposal is to determine whether existent immunity to HER-2/neu protein has diagnostic an prognostic significance as well as to identify the patient subgroups which might respond to therapeutic intervention with HER-2/neu reactive T cells. The specific aims are: (10 to examine CD4+ helper/inducer T cell responses to HER-2/neu protein; (2) to examine CD8+ cytotoxic T cell responses to HER-2/neu protein; and (3) to examine antibody responses to HER-2/neu protein.

HER-2/neu 原癌基因在 20-40% 的细胞中扩增并过度表达。浸润性乳腺癌。 HER-2/neu 过度表达与侵袭性疾病，是预后不良的独立预测因子患者的几个子集。 HER-2/neu也可能与癌症有关形成，在 50-60% 的导管中可检测到过度表达原位癌。我们实验室的总体目标是开发针对相关蛋白质的特异性 T 细胞疗法恶变。我们已经开始检查对 HER-2/neu 的免疫力乳腺癌患者的蛋白质。我们的初步研究发现一些乳腺癌患者存在 CD4+ 辅助/诱导 T 细胞免疫和抗体介导的针对 HER-2/neu 蛋白的免疫。它有假设正常人具有免疫耐受性致癌蛋白过度表达，无法产生免疫力；然而，如果能够产生免疫力，结果将是毁灭性的自身免疫。初步数据表明 HER-2/neu 反应性 T 细胞和抗体已经存在于乳腺的外周血中癌症患者意味着某些人体内诱导了对 HER-2/neu 的免疫力由于肿瘤生长而患有癌症的个体表达抗原并证实了 HER-2/neu- 特异性免疫可用于治疗而不破坏正常组织。检测对 HER-2/neu 的免疫力也可能提供一种方法乳腺癌的筛查和早期发现以及乳腺癌水平的变化免疫力可能与疾病状态相关并预测复发。其他初步研究表明，初级体外使用 HER-2/neu 肽片段进行免疫可引发 HER- 2/neu 肽特异性 CD8+ 细胞毒性 T 细胞 (CTL)。引出方法 HER-2/neu 肽特异性 CD8+ T 细胞应提供一种方法来确定乳腺癌患者是否存在对 HER- 的 CTL 反应 2/neu 并可能提供一种产生能够裂解的 CTL 的方法最终用于治疗的自体癌细胞。总体目标为该提案旨在确定是否存在对 HER-2/neu 的免疫力蛋白质具有诊断和预后意义以及识别可能对治疗干预有反应的患者亚组 HER-2/neu 反应性 T 细胞。具体目标是：（10 检查 CD4+ 辅助/诱导 T 细胞对 HER-2/neu 蛋白的反应； (2)检查CD8+ 细胞毒性 T 细胞对 HER-2/neu 蛋白的反应； (3) 检查针对 HER-2/neu 蛋白的抗体反应。