IMMUNITY TO HER-2/NEU PROTEIN IN BREAST CANCER

HER-2/neu原癌基因扩增和过度表达在20-40%的 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 患者的几个亚群。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 发展针对参与蛋白的特异性T细胞疗法 恶变。我们已经开始检查对她的免疫力-2/neu 乳腺癌患者体内的蛋白质。我们的初步研究发现 部分乳腺癌患者存在CD4+辅助性/诱导性T细胞 对HER-2/neu蛋白的细胞免疫和抗体介导的免疫。它有 一直认为正常人在免疫上会对 过表达致癌蛋白，不能产生免疫力； 然而，如果能够产生免疫力，结果将是破坏性的。 自身免疫力。初步数据显示HER-2/neu-反应T 乳房外周血中已经存在细胞和抗体。 癌症患者暗示对HER-2/neu的免疫力在某些 因肿瘤生长而罹患癌症的个人 表达抗原，并支持HER-2/neu- 特异性免疫可以在不破坏正常组织的情况下用于治疗。 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及其水平的变化 免疫力可能与疾病状态相关，并预测复发。 更多的初步研究表明，体外培养的初级细胞 用HER-2/neu多肽片段免疫可诱导HER-2- 2/neu多肽特异性CD8+细胞毒性T细胞(CTL)。引出的方法 HER-2/neu多肽特异性CD8+T细胞应该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，并且可以提供产生能够裂解的CTL的手段 最终用于治疗的自体癌细胞。的总目标是 这项提议是为了确定是否存在对HER-2/neu的免疫力 蛋白质具有诊断和预测预后的意义以及识别 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)检测CD4+ 辅助性/诱导性T细胞对HER-2/neu蛋白的应答；(2)检测CD8+ 细胞毒性T细胞对HER-2/neu蛋白的反应；和(3)检测 对HER-2/neu蛋白的抗体反应。

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.