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: 7689484
• 负责人: Cassian Yee
• 金额: $ 39.14万
• 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/7689484
• 关键词: Address; Alleles; Antigen Targeting; Antigen-Presenting Cells; Antigens; Cells; Disease; Disease Resistance; Early Diagnosis; Early treatment; Emerging Technologies; Evaluation; Expression Feature; Generations; Genetic Screening; Immune; Immune Targeting; Immune system; Immunity; Immunobiology; Immunologics; Immunotherapeutic agent; Immunotherapy; Laboratories; Language; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Methods; Modality; Molecular Analysis; Ovary; Patients; Peptides; Prevalence; Public Health; Recurrence; Relapse; Research; Residual Tumors; Resistance; Scanning; Screening procedure; T-Lymphocyte; Tumor Antigens; Tumor Immunity; Vaccination; base; cancer cell; chemotherapy; immunogenic; immunogenicity; improved; neoplastic cell; ovarian neoplasm; response; synthetic peptide combinatorial library; 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。大多数疾病患者最初对常规疗法有反应，但大多数人最终会因化学抗性疾病而复发。复发性卵巢癌通常无法治愈。基于免疫的治疗是治疗早期复发和残留疾病的潜在有效策略。不幸的是，促进对卵巢肿瘤免疫力的理解以及免疫治疗策略在治疗卵巢癌患者中的主要障碍一直是免疫原靶抗原的匮乏。对卵巢癌细胞表达的靶抗原的合理和全面评估将是可取的，并且可以从免疫学的角度对癌细胞的特征进行分子分析。与识别T细胞定义的抗原相关的实验障碍包括：1）使用肿瘤细胞（通常较差的抗原呈递细胞）作为刺激剂细胞； 2）与肿瘤反应性T细胞分离有关的困难； 3）鉴定T细胞识别的肿瘤抗原。这些障碍在我们的实验室和合作者中开发的新兴技术的应用反过来解决了。 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.这些研究的结果预计将产生各种定义明确的肿瘤抗原，这些肿瘤抗原的特征是其免疫原性，限制等位基因和表达的流行 - 这些特征因素考虑了候选抗原抗原靶标的细胞免疫疗法。我们预计，这些研究对于在理解卵巢癌的免疫生物学方面的研究中对于追踪患者的这种反应作为一种早期发现的手段以及通过肿瘤疫苗接种或产卵T细胞疗法试验来靶向治疗至关重要。研究与公共卫生的相关性（外行语言）：大多数卵巢癌死亡患有疾病的患者对化学疗法具有抗药性。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，很少有目标是由免疫系统瞄准的目标。我们已经开发了一种方法来有效鉴定卵巢癌的免疫靶标并增强其刺激癌症免疫力的能力。