Novel Strategy for Clinical Remission in Ovarian Cancer

卵巢癌临床缓解的新策略

• 批准号: 6952125
• 负责人: DAVID R SPRIGGS
• 金额: $ 10.28万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952125
• 关键词: carboplatin; carcinoma; cisplatin; clinical research; clinical trial phase I; clinical trial phase II; combination chemotherapy; drug resistance; heat shock proteins; human subject; human therapy evaluation; intraperitoneal injections; minimal residual disease; monoclonal antibody; mucins; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer remission /regression; neoplasm /cancer vaccine; nuclear factor kappa beta; ovary neoplasms; paclitaxel; patient oriented research; rifabutin; tumor antigens

Epithelial ovarian cancer (EOC) is a chemosensitive disease, yet remissions are often of short duration. The overall objective of this project is to evaluate novel methods of remission re-induction and maintenance, many of which are developed in other projects in this submission. The central theme relates to the recent identification of MUC16 and its possible role in the clinical behavior of ovarian cancer and chemotherapy resistance as well as using MUC16 as a potential therapeutic immunologic target. Investigational strategies are organized around a disease states model developed during the current PPG which allows groups of patients to be considered homogeneous for the purpose of evaluating therapeutic interventions. Specific aim 1 relates to the importance of achieving second complete clinical remission (cCR), in platinum sensitive patients, as an essential precursor to the evaluation of maintenance or consolidation therapy. The hypothesis is that molecularly targeted agents will increase the cCR, and separate clinical trials will evaluate the addition of Bortezomib (a proteosome inhibitor) and 17 allyl-aminogeldanamycin (targets Her-2 and AKT kinases). Exploration of the MUC16 contribution to chemotherapy resistance is also including in this aim. Patients in cCR have a predictably short response, and a series of cytostatic and immune based strategies are well suited for evaluation in this minimal disease state which serve as the focus of Specific Aim 2. Our first trial is a Phase II study of ACA125, an anti idiotype vaccine. We have previously identified a high frequency of Lewis Y positivity on ovarian cancer. We have initiated a Phase I trial of a Yt-hu3S193 humanized anti lewis Y antibody, given IP as consolidation. Regarding immune based therapies for remission, the culmination of a series of antibody producing monovalent vaccines explored in the current PPG has defined a consistently immunogenic polyvalent construct. A phase II efficacy trial will be performed in the complete remission population. Simultaneously, Phase I pilot trials evaluating T-cell activating vaccines; and the development of a MUC16 targeted vaccine are central to other projects in this submission. Specific Aim 3 relates to the importance of modeling CA-125 trajectory as a predictor of EOC biology which has been demonstrated in the current PPG, and the model will be prospectively validated. This aim has been enhanced by the inclusion of a new marker, YKL-40 in the prospective clinical trial on serum markers.

上皮性卵巢癌（EOC）是一种化学敏感性疾病，但缓解期通常很短。该项目的总体目标是评估缓解重新诱导和维持的新方法，其中许多方法是在本提交的其他项目中开发的。中心主题涉及 MUC16 的最新鉴定及其在卵巢癌临床行为和化疗耐药中的可能作用，以及使用 MUC16 作为潜在的治疗免疫靶点。研究策略是围绕当前 PPG 期间开发的疾病状态模型组织的，该模型允许将患者群体视为同质，以便评估治疗干预措施。具体目标 1 涉及在铂敏感患者中实现第二次完全临床缓解 (cCR) 的重要性，作为评估维持或巩固治疗的重要前提。假设分子靶向药物将提高 cCR，并且单独的临床试验将评估硼替佐米（一种蛋白酶体抑制剂）和 17 烯丙基氨基格尔德霉素（针对 Her-2 和 AKT 激酶）的添加。探索 MUC16 对化疗耐药性的贡献也包括在这一目标中。可以预见的是，cCR 患者的反应较短，一系列细胞抑制和基于免疫的策略非常适合在这种最小疾病状态下进行评估，这也是特定目标 2 的重点。我们的第一项试验是 ACA125 的 II 期研究，ACA125 是一种抗独特型疫苗。我们之前已经发现卵巢癌中 Lewis Y 阳性的频率很高。我们已经启动了 Yt-hu3S193 人源化抗路易斯 Y 抗体的 I 期试验，并以 IP 作为巩固。关于基于免疫的缓解疗法，当前 PPG 中探索的一系列产生抗体的单价疫苗的顶峰已经定义了一致的免疫原性多价构建体。将在完全缓解人群中进行 II 期疗效试验。同时，评估 T 细胞激活疫苗的 I 期试点试验； MUC16 靶向疫苗的开发是本次提交的其他项目的核心。具体目标 3 涉及 CA-125 轨迹建模作为 EOC 生物学预测因子的重要性，这已在当前的 PPG 中得到证明，并且该模型将得到前瞻性验证。通过在血清标志物前瞻性临床试验中纳入新标志物 YKL-40，这一目标得到了加强。