Novel Strategy for Clinical Remission in Ovarian Cancer

上皮性卵巢癌（EOC）是一种化学敏感性疾病，但缓解往往是短时间的。本项目的总体目标是评估缓解、再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。中心主题涉及最近MUC16的鉴定及其在卵巢癌临床行为和化疗耐药中的可能作用，以及将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，该模型允许将患者组视为同质，以评估治疗干预措施。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基本前兆。假设分子靶向药物会增加cCR，单独的临床试验将评估硼替佐米（一种蛋白体抑制剂）和17烯丙基氨基达霉素（靶向Her-2和AKT激酶）的添加。探索MUC16对化疗耐药的贡献也包括在这一目的中。cCR患者具有可预测的短反应，并且一系列基于细胞抑制剂和免疫的策略非常适合在这种最小疾病状态下进行评估，这是Specific Aim 2的重点。我们的第一个试验是抗独特型疫苗ACA125的II期研究。我们之前已经确定了卵巢癌中Lewis Y阳性的高频率。我们已经启动了一种Yt-hu3S193人源抗lewis Y抗体的I期试验，给予IP作为巩固。关于基于免疫的缓解疗法，目前PPG探索的一系列产生抗体的单价疫苗的高潮已经定义了一种一致的免疫原性多价结构。II期疗效试验将在完全缓解人群中进行。同时，评估t细胞活化疫苗的I期试点试验；以及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，这已经在当前的PPG中得到了证明，该模型将被前瞻性地验证。这一目标通过在血清标记物的前瞻性临床试验中纳入新的标记物YKL-40而得到加强。

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.