EPITOPE BASED T CELL THERAPY FOR EPITHELIAL TUMORS

表位为基础的T细胞治疗上皮性肿瘤。因为免疫力 系统具有识别并在许多情况下摧毁肿瘤的能力 细胞，正在致力于发展 基于免疫的癌症疗法。两种细胞毒性T淋巴细胞(CTL) 而辅助性T淋巴细胞(HTL)已被证明与抗原发生反应 通过肿瘤细胞表达，从而建立起保护性和 治疗效果。由于CTL和HTL识别抗原的形式为 具有主要组织相容性复合体(MHC)表面的多肽复合物 分子(人类中的人类白细胞抗原)，有必要确定其性质 肿瘤衍生多肽，可以激发T细胞反应，能够 抑制肿瘤细胞生长。 拟议研究的总体目标是识别多肽。 来源于几个已知的肿瘤相关抗原(TAA)的序列 这将能够刺激CTL和HTL对抗肿瘤细胞。我们 我选择了六种广泛表达在肿瘤细胞上的TAA 上皮来源：MAGE、CEA、HER2、HER3、P53、FAK。氨基酸 已经对这些TAA的序列进行了筛选，以确定是否存在多肽 含有MHC结合基序。相应的多肽将是 合成并检测其体外诱导T细胞的能力 对肿瘤细胞的反应和相应的TAA作为最终证据 它们真正代表了T细胞表位。我们工作的最终目标是 利用这些肿瘤反应性T细胞表位开发 常见上皮性癌的免疫治疗方法 (乳房、胃肠和肺)。为了实现这一目标，我们建议 以下具体目标：1-确定MHC I类-限制性CTL 常见于上皮癌的TAA表位；2-识别MHC 来自TAA的II类限制性辅助T细胞表位常见于 上皮性癌症；3.-增加CTL和T辅助免疫反应 通过表位重组获得TAA。这些目标的实现应 促进新的广泛适用的T细胞基础的开发 基于表位的疫苗和T细胞过继免疫治疗 治疗常见肿瘤的治疗方法。

Epitope-Based T-Cell Therapy for Epithelial Tumors. Because the immune system has the capacity to recognize and in many cases destroy tumor cells, significant efforts are being devoted to the development of immune-based therapies for cancer. Both cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) have been shown to react with antigens expressed by tumor cells and as a result establish protective and therapeutic effects. Since CTL and HTL recognize antigens in the form of peptide complexes with major histocompatibility complex (MHC) surface molecules (HLA in humans), it is necessary to identify the nature of tumor-derived peptides that can elicit T-cell responses capable of inhibiting tumor-cell growth. The overall objective of the proposed study is to identify peptides derived from sequences of several known tumor-associated antigens (TAA) that will be capable of stimulating CTL and HTL against tumor cells. We have selected six TAA that are widely expressed on tumor cells of epithelial origin: MAGE, CEA, HER2, HER3, p53 and FAK. The amino acid sequences of these TAA have been screened for the presence of peptides containing MHC binding motifs. Corresponding peptides will be synthesized and tested for their capacity to elicit in vitro T-cell responses to tumor cells and corresponding TAA as a final proof that they truly represent T-cell epitopes. The ultimate goal of our work is to utilize these tumor-reactive T-cell epitopes to develop immunotherapeutic approaches to treat commonly found epithelial cancers (breast, gastrointestinal and lung). To accomplish this goal, we propose the following specific aims: 1-identify MHC class I-restricted CTL epitopes from TAA commonly found on epithelial cancers; 2-Identify MHC class II-restricted helper T-cell epitopes from TAA commonly found on epithelial cancers; 3.- Increase CTL and T helper immune responses to TAA's by epitope re-engineering. The completion of these aims should facilitate the development of novel broadly applicable T-cell based immune therapies such as epitope-based vaccines and T-cell adoptive therapy for the treatment of frequently encountered tumors.