Novel target antigens for ovarian cancer immunotherapy

卵巢癌免疫治疗的新靶抗原

• 批准号: 6933008
• 负责人: Martin J Cannon
• 金额: $ 26.2万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-09 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933008
• 关键词: clinical research; cytolysins; cytolysis; cytotoxic T lymphocyte; dendritic cells; flow cytometry; gene expression; helper T lymphocyte; human subject; immunotherapy; metalloendopeptidases; ovary neoplasms; pore forming protein; serine proteinases; tumor antigens

DESCRIPTION (provided by applicant): Two-thirds of ovarian cancer patients have advanced disease at the time of diagnosis, and ovarian cancer has the highest mortality rate among gynecological malignancies. Immunotherapy based on induction of tumor-specific cytotoxic T lymphocyte (CTL) responses may represent an attractive option for these patients. We have identified a series of novel ovarian tumor antigens, including the tumor-associated differentially expressed gene 14 (TADG-14) product, TADG-15, hepsin, stratum corneum chymotryptic enzyme (SCCE), all of which are serine proteases, and the matrix metalloprotease, pump-l. These antigens are highly expressed in ovarian cancer but not in normal ovaries or the majority of other normal adult tissues, suggesting that they may be excellent target antigens for dendritic cell (DC) immunotherapy. This proposal will test the hypothesis that antigen or peptide-loaded DC can be used to induce specific T lymphocyte responses from patients with ovarian cancer, and that tumor antigen-specific CTL will lyse ovarian tumor cells. We have shown that peptide-loaded DC stimulate HLA class I-restricted CDS+ CTL that lyse antigen-expressing targets, including HLA-matched ovarian tumor cells. The 1st Specific Aim will identify further CTL epitopes and determine whether DC-stimulated peptide-specific CD8+ CTL from ovarian cancer patients lyse ovarian tumor cells. We will also test whether DC transfected with novel HLA class I single chain trimers induce peptide-specific CD8+ CTL responses. In the 2nd Specific Aim, we will construct peptides that encompass defined CTL epitopes and candidate CD4+ helper T cell epitopes with degenerate HLA class II binding potential. DC loaded with multi-epitope peptides will be tested for their ability to induce antigen-specific CD8+ CTL responses and CD4+ helper T cell responses. The rationale for this strategy is that antigen-specific CD4+ T cells provide essential help for the induction and maintenance of effective CD8+ T cell responses in vivo. We will also test the immunogenicity of peptides translated from recently discovered intron sequences expressed in variant hepsin and TADG-14. The 3rd Specific Aim will determine whether DC loaded with full-length recombinant tumor antigen or transfected with linear DNA constructs induce CD8+ CTL and CD4+ T cell responses from ovarian cancer patients. This proposal is targeted at the development of clinical trial protocols for therapeutic DC vaccination for prevention of progression of ovarian cancer.

描述（由申请人提供）：三分之二的卵巢癌患者在诊断时患有病晚期疾病，而卵巢癌在妇科恶性肿瘤中的死亡率最高。基于诱导肿瘤特异性细胞毒性T淋巴细胞（CTL）反应的免疫疗法可能是这些患者的有吸引力的选择。我们已经确定了一系列新型的卵巢肿瘤抗原，包括与肿瘤相关的差异表达的基因14（TADG-14）产物，TADG-15，TADG-15，Hepsin，Corneum Cornum chymotrypryptic酶（SCCE），所有这些都是丝氨酸蛋白酶，以及Matrix Metrix Melallopotease，Melallix Metallallopotease，pup pup-l。这些抗原在卵巢癌中高度表达，但在正常卵巢或其他大多数正常成年组织中不表达，这表明它们可能是树突状细胞（DC）免疫疗法的极好的靶抗原。该提案将检验以下假设：抗原或肽的DC可用于诱导卵巢癌患者的特定T淋巴细胞反应，并且肿瘤抗原特异性CTL会裂解卵巢肿瘤细胞。我们已经表明，肽负载的DC刺激了I限制的CDS+ CTL的HLA，其表达抗原的靶标，包括HLA匹配的卵巢肿瘤细胞。第一个特定目标将确定进一步的CTL表位，并确定DC刺激的肽特异性CD8+ CTL是否来自卵巢癌患者裂解卵巢肿瘤细胞。我们还将测试DC使用新型HLA I类单链三聚体转染的DC是否诱导肽特异性CD8+ CTL响应。在第二个特定目的中，我们将构建具有定义的CTL表位和候选CD4+ Helper T细胞表位的肽，具有脱位HLA II类结合潜力。带有多型肽肽的直流将测试其诱导抗原特异性CD8+ CTL响应和CD4+辅助辅助T细胞反应的能力。该策略的理由是，抗原特异性CD4+ T细胞为体内有效CD8+ T细胞反应的诱导和维持提供了必不可少的帮助。我们还将测试从变异性肝素和tadg-14中表达的最近发现的内含子序列翻译的肽的免疫原性。第三个特定目标将确定DC是否装有全长重组肿瘤抗原或用线性DNA构建体转染的DC诱导CD8+ CTL和CD4+ T细胞反应来自卵巢癌患者。该提案针对的是开发用于预防卵巢癌进展的治疗DC疫苗治疗方案。