Identification of T Cell-Defined Antigens in Ovarian Cancer

卵巢癌中 T 细胞定义的抗原的鉴定

• 批准号: 7905974
• 负责人: Cassian Yee
• 金额: $ 39.13万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905974
• 关键词: Address; Affinity; Alleles; Anatomy; Antibodies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autologous; Autologous Dendritic Cells; Biometry; Cell Line; Cell Therapy; Cells; Charge; Clinic; Cloning; Complementary DNA; Data; Disease; Disease Resistance; Early Diagnosis; Early treatment; Emerging Technologies; Epitopes; Evaluation; Fostering; Generations; Genetic Screening; Goals; Immune; Immune Targeting; Immune response; Immune system; Immunity; Immunobiology; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Laboratories; Language; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modality; Molecular; Molecular Analysis; Molecular Profiling; Mutagenesis; Ovary; Patients; Peptide Library; Peptides; Phase; Prevalence; Public Health; Recurrence; Relapse; Renal Cell Carcinoma; Research; Research Personnel; Residual Tumors; Resistance; Role; Scanning; Screening procedure; Solid Neoplasm; Specificity; Subcellular Anatomy; System; T cell response; T-Lymphocyte; Technology; Technology Transfer; Transfection; Tumor Antigens; Tumor Cell Line; Tumor Immunity; Tumor Tissue; Tumor-Derived; Vaccination; advanced disease; anticancer research; base; cDNA Library; cancer cell; cancer therapy; chemotherapy; combinatorial; conventional therapy; immunogenic; immunogenicity; improved; melanoma; neoplastic cell; novel; ovarian neoplasm; programs; response; synthetic peptide combinatorial library; treatment strategy; tumor

DESCRIPTION (provided by applicant): Immunotherapy of ovarian cancer represents an emerging modality for the treatment of patients with advanced disease. The majority of patients with disease spread beyond the ovaries initially respond to conventional therapy, but most will eventually relapse with chemo-resistant disease; recurrent ovarian cancer is generally incurable. Immune-based therapy represents a potentially effective strategy in the treatment of early relapse and residual disease. Unfortunately, a major obstacle to advancing the understanding of ovarian tumor immunity and the application of immunotherapeutic strategies for the treatment of patients with ovarian cancer has been the paucity of immunogenic target antigens. A rational and comprehensive evaluation of target antigens expressed by ovarian cancer cells would be desirable and would permit a molecular analysis of the profile of cancer cells from an immunologic perspective. Experimental hurdles associated with identifying T cell- defined antigens include: 1) the use of tumor cells (typically poor antigen presenting cells) as stimulator cells; 2) the difficulties associated with the isolation of tumor-reactive T cells; and 3) the identification of tumor antigens recognized by T cells. Each of these obstacles is addressed in turn through the application of emerging technologies developed in our laboratory and that of our collaborators. These have led to improved strategies for the generation of tumor-reactive antigen-specific T cells using opsonized tumor cell- derived antigens, the direct isolation of T cell clones and expansion for characterization and screening, and the use of a positional scanning synthetic combinatorial peptide libraries to identify T cell targets, and the use of high-throughput genetic screening to identify functionally enhancing altered peptide ligands. The results of these studies are expected to yield a diverse panel of well-defined tumor antigens that have been characterized for their immunogenicity, restricting allele, and prevalence of expression - features that factor into the consideration of candidate antigen targets for cellular immunotherapy. We anticipate that these studies will be essential for advancing research in understanding the immunobiology of ovarian cancer for tracking such responses in patients as a means of early detection and for targeting therapies by tumor vaccination or adoptive T cell therapy trials. Relevance of Research to Public Health (lay language): Most patients with ovarian cancer die of disease that is resistant to chemotherapy. The immune system may be used to treat patients with recurrent ovarian cancer. One of the major obstacles to this strategy is that very few targets are known which can be targeted by the immune system. We have developed a method to efficiently identify immune targets for ovarian cancer and enhance their ability to stimulate cancer immunity.

描述（由申请人提供）：卵巢癌的免疫疗法代表了治疗晚期疾病患者的新兴方式。大多数疾病扩散到卵巢以外的患者最初对常规治疗有反应，但大多数最终会因化疗耐药而复发；复发性卵巢癌通常是无法治愈的。基于免疫的治疗代表了治疗早期复发和残留疾病的潜在有效策略。不幸的是，推进对卵巢肿瘤免疫的理解和应用免疫治疗策略治疗卵巢癌患者的一个主要障碍是缺乏免疫原性靶抗原。对卵巢癌细胞表达的靶抗原进行合理和全面的评估将是可取的，并且将允许从免疫学角度对癌细胞的概况进行分子分析。与鉴定 T 细胞定义的抗原相关的实验障碍包括：1) 使用肿瘤细胞（通常是较差的抗原呈递细胞）作为刺激细胞； 2）与肿瘤反应性T细胞分离相关的困难； 3) T细胞识别的肿瘤抗原的鉴定。这些障碍中的每一个都通过应用我们实验室和我们的合作者开发的新兴技术来解决。这些改进了使用调理肿瘤细胞衍生抗原生成肿瘤反应性抗原特异性 T 细胞、直接分离 T 细胞克隆和扩展以进行表征和筛选以及使用位置扫描合成组合肽的策略文库来识别 T 细胞靶标，并使用高通量遗传筛选来识别功能增强的改变的肽配体。这些研究的结果预计将产生一系列明确的肿瘤抗原，这些抗原的特征在于其免疫原性、限制性等位基因和表达流行率——这些特征是考虑细胞免疫治疗候选抗原靶点的因素。我们预计这些研究对于推进了解卵巢癌免疫生物学的研究至关重要，以跟踪患者的此类反应作为早期检测的手段，并通过肿瘤疫苗接种或过继性 T 细胞治疗试验进行靶向治疗。研究与公共卫生的相关性（外行语言）：大多数卵巢癌患者死于对化疗有抵抗力的疾病。免疫系统可用于治疗复发性卵巢癌患者。该策略的主要障碍之一是已知的免疫系统可以靶向的靶标很少。我们开发了一种方法来有效识别卵巢癌的免疫靶点并增强其刺激癌症免疫的能力。