Identification of T Cell-Defined Antigens in Ovarian Cancer

描述（由申请人提供）：卵巢癌的免疫治疗代表了晚期疾病患者治疗的一种新兴模式。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，但大多数最终会复发为化疗耐药疾病；复发性卵巢癌一般无法治愈。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的理解和应用免疫治疗策略治疗卵巢癌患者的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价是可取的，并将允许从免疫学角度对癌细胞的分子特征进行分析。与鉴定T细胞定义抗原相关的实验障碍包括：1)使用肿瘤细胞（通常是差抗原提呈细胞）作为刺激细胞；2)与分离肿瘤反应性T细胞相关的困难；3) T细胞识别的肿瘤抗原的鉴定。通过应用我们实验室和我们的合作者开发的新兴技术，我们依次解决了这些障碍。这些已经导致了使用opsonized肿瘤细胞衍生抗原产生肿瘤反应性抗原特异性T细胞的改进策略，T细胞克隆的直接分离和扩增用于表征和筛选，以及使用位置扫描合成组合肽文库来识别T细胞靶标，以及使用高通量遗传筛选来识别功能增强的改变肽配体。这些研究的结果有望产生一系列定义明确的肿瘤抗原，这些抗原以其免疫原性、限制性等位基因和表达的普遍性为特征，这些特征是考虑细胞免疫治疗候选抗原靶点的因素。我们预计这些研究将对了解卵巢癌的免疫生物学研究至关重要，以跟踪患者的这种反应，作为早期检测的手段，并通过肿瘤疫苗接种或过继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耐药性的疾病。免疫系统可用于治疗复发性卵巢癌患者。这一策略的主要障碍之一是，很少有已知的目标可以被免疫系统靶向。我们已经开发出一种方法来有效地识别卵巢癌的免疫靶点，并增强它们刺激癌症免疫的能力。

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.