Identification of T Cell-Defined Antigens in Ovarian Cancer

描述(由申请人提供)：卵巢癌的免疫疗法代表了一种治疗晚期疾病患者的新兴方法。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，但大多数人最终会因耐药疾病而复发；复发的卵巢癌通常是无法治愈的。基于免疫的治疗是治疗早期复发和残留疾病的一种潜在的有效策略。不幸的是，缺乏免疫原靶抗原一直是提高对卵巢肿瘤免疫的了解和应用免疫治疗策略治疗卵巢癌患者的主要障碍。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，并将使从免疫学角度对癌细胞的特征进行分子分析成为可能。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(通常是较差的抗原提呈细胞)作为刺激细胞；2)与分离肿瘤反应性T细胞有关的困难；以及3)识别T细胞识别的肿瘤抗原。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。这导致了使用调理的肿瘤细胞来源的抗原产生肿瘤反应性抗原特异性T细胞的改进策略，直接分离和扩增T细胞克隆并用于鉴定和筛选，使用位置扫描合成组合多肽库来识别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的多肽配体。这些研究的结果有望产生一组定义明确的肿瘤抗原，这些抗原的特点是免疫原性、限制性等位基因和表达的普遍性--这些特征是考虑细胞免疫治疗的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、跟踪患者的这种反应作为早期发现的手段以及通过肿瘤疫苗或过继T细胞治疗试验进行靶向治疗将是必不可少的。研究与公共卫生的相关性(通俗语言)：大多数卵巢癌患者死于对化疗有抗药性的疾病。免疫系统可能被用于治疗复发的卵巢癌患者。这一策略的主要障碍之一是，几乎没有人知道免疫系统可以靶向的靶点。我们已经开发出一种方法，可以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.