Novel target antigens for ovarian cancer immunotherapy

卵巢癌免疫治疗的新靶抗原

• 批准号: 6826415
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826415
• 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（申请人提供）：三分之二的卵巢癌患者在诊断时已处于晚期，卵巢癌是妇科恶性肿瘤中死亡率最高的。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对这些患者来说是一种有吸引力的选择。我们鉴定了一系列新型卵巢肿瘤抗原，包括肿瘤相关差异表达基因14（TADG-14）产物、TADG-15、hepsin、角质层胰凝乳蛋白酶（SCCE），它们都是丝氨酸蛋白酶，以及基质金属蛋白酶，泵-l。这些抗原在卵巢癌中高度表达，但在正常卵巢或大多数其他正常成人组织中不表达，这表明它们可能是树突状细胞（DC）免疫治疗的极好靶抗原。该提案将检验以下假设：抗原或肽负载 DC 可用于诱导卵巢癌患者的特异性 T 淋巴细胞反应，并且肿瘤抗原特异性 CTL 将裂解卵巢肿瘤细胞。我们已经证明，负载肽的 DC 会刺激 HLA I 类限制性 CDS+ CTL，从而裂解表达抗原的靶标，包括 HLA 匹配的卵巢肿瘤细胞。第一个具体目标将进一步鉴定 CTL 表位，并确定来自卵巢癌患者的 DC 刺激肽特异性 CD8+ CTL 是否会裂解卵巢肿瘤细胞。我们还将测试用新型 HLA I 类单链三聚体转染的 DC 是否诱导肽特异性 CD8+ CTL 反应。在第二个具体目标中，我们将构建包含确定的 CTL 表位和具有简并 HLA II 类结合潜力的候选 CD4+ 辅助 T 细胞表位的肽。将测试装载多表位肽的 DC 诱导抗原特异性 CD8+ CTL 反应和 CD4+ 辅助 T 细胞反应的能力。该策略的基本原理是抗原特异性 CD4+ T 细胞为体内有效 CD8+ T 细胞反应的诱导和维持提供必要的帮助。我们还将测试从最近发现的在变体 hepsin 和 TADG-14 中表达的内含子序列翻译的肽的免疫原性。第三个具体目标将确定负载全长重组肿瘤抗原的 DC 或用线性 DNA 构建体转染的 DC 是否诱导卵巢癌患者的 CD8+ CTL 和 CD4+ T 细胞应答。该提案旨在制定用于预防卵巢癌进展的治疗性 DC 疫苗接种的临床试验方案。