IMMUNITY TO HER-2/NEU PROTEIN IN BREAST CANCER

HER-2/neu原癌基因在20-40%的人中扩增和过表达， 浸润性乳腺癌 HER-2/neu过表达与 侵袭性疾病，是预后不良的独立预测因子， 几个病人的子集。 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 开发特异性T细胞疗法，针对参与 恶性转化 我们已经开始检查对HER-2/neu的免疫力 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CD 4+辅助/诱导T细胞， 细胞免疫和抗体介导的HER-2/neu蛋白免疫。 它有 假设正常个体对以下疾病具有免疫耐受性： 过度表达致癌蛋白，不能产生免疫; 然而，如果能够产生免疫力，结果将是破坏性的， 自身免疫 初步数据表明HER-2/neu反应性T细胞 细胞和抗体已经存在于乳腺癌的外周血中 癌症患者中的某些人对HER-2/neu的免疫力被诱导， 由于存在生长的肿瘤， 表达抗原，并证实HER-2/neu- 特异性免疫可用于治疗而不破坏正常组织。 HER-2/neu免疫力的检测也可能提供一种方法， 筛查和早期发现乳腺癌以及 免疫力可能与疾病状态和预测复发相关。 额外的初步研究表明， HER-2/neu肽片段的免疫可用于引发HER-2/neu肽片段。 2/neu肽特异性CD 8+细胞毒性T细胞（CTL）。 方法引出 HER-2/neu肽特异性CD 8 + T细胞应该提供一种方法， 乳腺癌患者是否存在针对HER的CTL应答， 2/neu，并且可以提供产生能够裂解 自体癌细胞用于最终治疗。 的总目标 这项建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后意义， 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CD 4 + 辅助/诱导T细胞对HER-2/neu蛋白的应答;（2）检测CD 8 + 细胞毒性T细胞对HER-2/neu蛋白的应答;以及（3）检测 HER-2/neu蛋白的抗体应答。

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.