Mesothelin as biomarker and therapeutic target

间皮素作为生物标志物和治疗靶点

• 批准号: 7686177
• 负责人: INGEGERD E HELLSTROM
• 金额: $ 27万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-11 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686177
• 关键词: Affect; Animal Model; Antibodies; Antigen-Antibody Complex; Antigens; Autoimmunity; Biological Assay; Biological Markers; Body Fluids; CA-125 Antigen; Cancer Immunology Science; Cells; Chickens; Clinical; Complement; Complement-Dependent Cytotoxicity; Data; Diagnosis; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Goals; Gold; Human; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Malignant neoplasm of ovary; Measures; Mediating; Mesothelioma; Oophoritis; Ovarian; Ovarian Carcinoma; Pancreatic carcinoma; Patient Monitoring; Patients; Relative (related person); Serum; Staging; TNFRSF5 gene; Testing; Therapeutic; Tumor Escape; Vaccination; Variant; Woman; Work; advanced disease; base; cytotoxicity; effective therapy; egg; human subject; improved; mesothelin; neoplastic cell; novel; outcome forecast; overexpression; public health relevance; research study; response; therapeutic target; tumor

DESCRIPTION (provided by applicant): Our overall goal is to gain better understanding of the immune response to ovarian carcinoma (OvC) and make possible earlier diagnosis and more effective therapy. Several years ago we constructed an ELISA to detect mesothelin in body fluids and showed that it may aid in the diagnosis of tumors which express this molecule, including OvC, to satisfy a great clinical need. We subsequently found that the molecule shed from tumor cells and detected by the ELISA is mesothelin variant 1. We recently constructed an assay for antibodies to native mesothelin. Preliminary data indicate that the antibodies are most frequent in OvC patients who are temporarily tumor-free following therapy and in younger women with ovarian autoimmunity (oophoritis), and that circulating antibodies and antigen coexist in some patients with advanced disease. Based on these findings, we hypothesize that when antigen concentrations are low (as in early stage disease), free antibodies are in excess and are more readily measured while in the presence of tumors expressing mesothelin, antigen is in excess and is more readily measured. Measuring both antigen and antibodies may aid diagnosis and monitoring of patients with OvC. Furthermore, the relative availability of antibodies and their ability to influence the host response may change during the course of disease and may affect therapeutic strategies, including immunotherapeutic approaches. We also hypothesize that circulating mesothelin, alone and as part of immune complexes, can facilitate the escape of tumors from immunological control by a mechanism that may involve immature APC and Treg cells, and that vaccination against mesothelin can be beneficial. We propose to test these hypotheses under three Specific Aims. First, we will investigate whether the levels of mesothelin and anti-mesothelin antibodies in sera from patients with OvC and women with ovarian autoimmunity correlate with their clinical state to aid diagnosis and prognosis. Second, we will evaluate mesothelin as a target for humoral and cell-mediated host responses to OvC. Third, we will study in egg-laying hens, which spontaneously develop OvC similar to the human counterpart, the relationship between circulating mesothelin and anti-mesothelin antibodies to tumor formation OvC and investigate whether the occurrence of OvC can be delayed or abrogated by vaccination against mesothelin. Our proposed study is based on novel observations, combines expertise in cancer immunology and autoimmunity and comprises studies both with human subjects and in an appropriate animal model. While we focus on OvC, the information obtained should be relevant also for other tumors that overexpress mesothelin, including mesothelioma and pancreatic carcinoma. PUBLIC HEALTH RELEVANCE: Earlier work by our group has demonstrated that most ovarian cancers express mesothelin and led to an assay that complements the previous `gold standard' CA125 to facilitate diagnosis. We have recently constructed an assay to measure antibodies to mesothelin to improve diagnosis. The proposed work aims to evaluate this assay and also to develop immunotherapy targeting mesothelin.

描述（由申请人提供）：我们的总体目标是更好地了解对卵巢癌（OVC）的免疫反应，并使早期诊断和更有效的治疗可能。几年前，我们构建了一个ELISA，以检测体液中的间皮素，并表明它可能有助于诊断表达该分子（包括OVC）的肿瘤，以满足巨大的临床需求。随后，我们发现从肿瘤细胞中脱落并被ELISA检测到的分子是间皮素变体1。初步数据表明，在治疗后暂时不含肿瘤的OVC患者和卵巢自身免疫性（卵巢炎），并且在某些患有晚期疾病的患者中，抗体最常见。基于这些发现，我们假设抗原浓度低（如早期疾病中）时，游离抗体的过量且在表达间皮素的肿瘤存在下更容易测量，抗原会过高，并且更容易测量。测量抗原和抗体可能有助于诊断和监测OVC患者。此外，抗体的相对可用性及其影响宿主反应的能力在疾病过程中可能会发生变化，并可能影响治疗策略，包括免疫治疗方法。我们还假设单独循环间皮素（作为免疫复合物的一部分）可以通过一种可能涉及未成熟APC和Treg细胞的机制来促进肿瘤从免疫控制中逃脱，并且针对间皮素的疫苗接种可能是有益的。我们建议在三个特定目标下检验这些假设。首先，我们将研究来自OVC患者和卵巢自身免疫性女性的血清中间皮素和抗中皮蛋白抗体的水平是否与其临床状态相关以帮助诊断和预后。其次，我们将评估间皮素作为对OVC的体液和细胞介导的宿主反应的靶标。第三，我们将研究卵子母鸡，它们自发发展与人类对应物相似的OVC，循环间皮素和抗中皮素抗体与肿瘤形成OVC的关系之间的关系，并研究OVC的发生是否可以通过抗蛋白皮素来延迟或消除OVC的发生。我们提出的研究是基于新颖的观察结果，结合了癌症免疫学和自身免疫性的专业知识，并包括与人类受试者和适当的动物模型的研究。尽管我们专注于OVC，但获得的信息也应与其他过表达间皮素（包括间皮瘤和胰腺癌）过表达的肿瘤有关。公共卫生相关性：我们小组的较早工作表明，大多数卵巢癌表达间皮素，并导致一种对以前的“黄金标准” CA125进行补充以促进诊断的测定法。最近，我们构建了一种测定测定的测定法，以测量间皮素的抗体以改善诊断。拟议的工作旨在评估该测定法，并开发针对间皮素的免疫疗法。