A NEW TARGET FOR IMMUNOTHERAPY OF CANCER

癌症免疫治疗的新靶点

• 批准号: 6889888
• 负责人: BORIS MINEV
• 金额: $ 13.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6889888
• 关键词: T cell receptor; antigen presentation; antigens; biotechnology; clinical research; cytotoxic T lymphocyte; dendritic cells; endoplasmic reticulum; enzyme linked immunosorbent assay; flow cytometry; human subject; immune response; immunofluorescence technique; major histocompatibility complex; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; peptides; proteolysis; survivin; synthetic vaccines; vaccine development

The cytotoxic T lymphocytes (CTL) appear to be among the most direct and effective elements of the immune system that are capable of generating anti-tumor immune responses. A fast growing number of reports demonstrate the presence of anti-tumor CTL in peripheral blood from patients with cancer. Recently, a novel gene, named survivin, that is highly expressed in many types of cancer has been identified. Survivin may be an ideal target for immunotherapy of many human tumors because of its strong expression in cancer, little or no expression in adult tissues, and its essential role for the survival of the tumor cells. In the current proposal we plan to identify immunogenic survivin-derived peptides. We will also focus on the further development of optimized synthetic vaccines for cancer based on this antigen. The goals of this study are to design optimized synthetic vaccines based on several class I restricted, survivin-derived peptides. We will utilize several modern approaches for vaccine design, including terminal modifications to inhibit proteolytic degradation of the peptides, amino acid substitutions to enhance the MHC binding affinity and the T cell receptor binding affinity of these peptides, and endoplasmic reticulum insertion signal sequences to enhance their antigen presentation. We will then use these vaccines to generate in vitro antigen-specific CTL lines and clones from healthy volunteers and from patients with cancer. We will test the ability of these antigen-specific CTL to kill cancer cells in a class I-restricted and antigen-dependent fashion. In some of the experiments we will use human dendritic cells to induce antigen-specific CTL in vitro. We will also analyze carefully all data for statistical significance. The design of optimized vaccines based on survivin-derived peptides will undoubtedly contribute to the development of more efficient approaches for treatment of cancer. These vaccines might be used directly to immunize patients with cancer. Dendritic cells loaded with these vaccines can also be used to elicit powerful anti-tumor immune responses. In addition, antigen-specific CTL might be extremely useful for cellular immunotherapy of cancer. Therefore, the findings of this study will be used in translational and clinical programs that will benefit patients with many types of cancer expressing survivin.

细胞毒性T淋巴细胞（CTL）似乎是能够产生抗肿瘤免疫反应的免疫系统中最直接，最有效的元素之一。快速增长的报告表明，癌症患者的外周血中存在抗肿瘤CTL。最近，已经确定了一个名为Survivin的新型基因，该基因在许多类型的癌症中得到了高度表达。 Survivin可能是许多人类肿瘤免疫疗法的理想靶标，因为它在癌症中表现强，在成年组织中很少或没有表达以及其在肿瘤细胞存活中的重要作用。在当前的建议中，我们计划鉴定免疫原性的源自生存的肽。我们还将重点关注基于该抗原的癌症优化合成疫苗的进一步开发。这项研究的目标是 设计基于几个I类限制的，源自生存的肽的优化合成疫苗。我们将利用几种现代方法进行疫苗设计，包括末端修饰来抑制肽的蛋白水解降解，氨基酸取代，以增强这些肽的MHC结合亲和力以及这些肽的T细胞受体结合亲和力，以及内胞质网状插入信号序列，以增强其抗原剂的伴侣。然后，我们将使用这些疫苗来产生来自健康志愿者和癌症患者的体外抗原特异性CTL线和克隆。我们将测试这些抗原特异性的能力 CTL以I级限制和抗原依赖性的方式杀死癌细胞。在某些实验中，我们将使用人树突状细胞在体外诱导抗原特异性CTL。我们还将仔细分析所有数据的统计意义。 基于生存衍生肽的优化疫苗的设计无疑将有助于开发更有效的癌症治疗方法。这些疫苗可直接用于免疫癌症患者。装有这些疫苗的树突状细胞也可用于引起强大的抗肿瘤免疫反应。此外，抗原特异性CTL可能对癌症的细胞免疫疗法非常有用。因此，这项研究的发现将用于转化和临床计划，这些计划将使许多表达Survivin的癌症患者受益。