EPITOPE BASED T CELL THERAPY FOR EPITHELIAL TUMORS

基于表位的T细胞治疗上皮性肿瘤。因为免疫 系统具有识别并在许多情况下破坏肿瘤的能力 细胞，重大努力正在致力于发展 癌症的免疫疗法细胞毒性T淋巴细胞（CTL） 和辅助性T淋巴细胞（HTL）已被证明与抗原反应 肿瘤细胞表达，并因此建立保护性和 治疗效果由于CTL和HTL识别抗原的形式是 具有主要组织相容性复合物（MHC）表面的肽复合物 分子（人类的HLA），有必要确定的性质， 可以引发T细胞应答的肿瘤衍生肽， 抑制肿瘤细胞生长。 拟议研究的总体目标是鉴定肽 来源于几种已知的肿瘤相关抗原（TAA）的序列 能够刺激CTL和HTL对抗肿瘤细胞。我们 我们选择了六种广泛表达在肿瘤细胞上的TAA， 上皮来源：法师、CEA、HER 2、HER 3、p53和FAK。的氨基酸 这些TAA的序列已经被筛选出存在肽 含有MHC结合基序。相应的肽将是 合成并测试其体外诱导T细胞增殖的能力。 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， 治疗常见上皮癌的免疫方法 （乳腺、胃肠道和肺）。为了实现这一目标，我们建议 具体目的如下：1-鉴定MHC I类限制性CTL 来自上皮癌上常见的TAA的表位; 2-鉴定MHC 来自TAA的II类限制性辅助性T细胞表位通常在 上皮癌; 3.增加CTL和T辅助免疫应答， 通过表位再工程的TAA。这些目标的实现应 促进开发新的广泛适用的基于T细胞的 免疫疗法，如基于表位的疫苗和T细胞过继性 用于治疗常见肿瘤的疗法。

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.