RPCI-UPCI Ovarian Cancer SPORE

描述(由申请人提供)：罗斯威尔大学公园癌症研究所(RPCI)和匹兹堡大学(UPCI)卵巢癌孢子的总体目标是通过创新的翻译研究降低卵巢癌的发病率和死亡率。它包括四个单独的研究项目，四个支持性核心，以及研究和职业发展计划。这项建议汇集了基础和应用调查人员，以进行旨在风险分层、治疗等方面的创新和多样化的翻译调查 预防原发和复发卵巢癌，以及预防缓解期患者复发。这四个项目经过精心设计，具有在五年内改变卵巢癌临床实践范例的巨大潜力。该计划的主题独特地反映了基于免疫的方法在卵巢癌患者的病因、预后和治疗中的作用。拟议的项目将：1)测试一种新的治疗策略，以打破吲哚胺2，3-双加氧酶(IDO)介导的卵巢癌免疫耐受，同时在二次缓解患者中诱导抗肿瘤特异性免疫(项目1)；2)测试mTOR抑制和IL-21的组合策略，用于体外调节抗原刺激的CD8 T细胞的效应和记忆功能；以及在临床试验中测试体外生成的细胞是否对卵巢肿瘤产生持久的免疫；3)检测自体肿瘤负载的1型极化树突状细胞(DC1s)是否能够产生能够以MHC I类限制性或MHC I类L非限制性方式识别卵巢癌的CTL；当同时用作疫苗和过继T细胞治疗时(项目3)；确定髓系衍生抑制细胞(MDSC)对卵巢癌患者长期生存具有强大的免疫抑制特性的预测意义(项目4)。每个项目至少涉及孢子指南中概述的一个翻译领域，该计划共同解决翻译研究工作组定义的翻译途径。四个核心将支持这些项目：管理、生物医学、生物统计和医学信息学、免疫监测。发展研究计划将支持一条继续确定和支持可能取代或改进现有项目的多样化研究的途径，职业发展计划将招募和支持致力于卵巢癌翻译研究培训的候选人。发展研究计划和职业发展计划将提供一个框架，指导年轻的研究人员在卵巢癌翻译研究中发展事业，并使高风险、潜在的范例改变项目的测试具有翻译潜力。

DESCRIPTION (provided by applicant): The overall goal of the University of the Roswell Park Cancer Institute (RPCI) and University of Pittsburgh (UPCI) Ovarian Cancer SPORE is to reduce the morbidity and mortality of ovarian cancer through innovative translational research. It includes four individual research projects, four supportive cores, and research and career development programs. This proposal brings together basic and applied investigators to conduct innovative and diverse translational investigations aimed at risk stratification, treatment of primary and recurrent ovarian cancer, and prevention of relapse in patients in remission. The four projects have been carefully designed to have significant potential to change clinical practice paradigms in ovarian cancer within five years. The theme of the program uniquely reflects immune based approaches in the etiology, prognosis and treatment of patients with ovarian cancer. The proposed projects will: 1) Test a novel therapeutic strategy to break indoleamine 2,3-dioxygenase (IDO)-mediated immune tolerance in ovarian cancer, while inducing anti-tumor-specific immunity in patients in second remission (Project 1); 2) Test a combinatorial strategy of mTOR inhibition and IL-21 for ex-vivo conditioning of antigen stimulated CD8+ T cells for effector and memory functional attributes; and test whether the ex vivo generated cells produce durable immunity against ovarian tumor in a clinical trial (Project 2); 3) Test whether autologous tumor-loaded type-1-polarized dendritic cells (¿DC1s) will generate CTLs capable of recognizing ovarian cancer in either MHC class I-restricted- or MHC class l-unrestricted fashion; when used both as a vaccine and for adoptive T cell therapy (Project 3); Determine the predictive significance of myeloid derived suppressor cells (MDSCs), which have strong immunosuppressive properties in the long term survival of ovarian cancer patients (Project 4). Each project addresses at least one of the translational areas outlined in the SPORE guidelines and together, the program addresses the translational pathways defined by the Translational Research Working Group. Four Cores will support these projects: Administration, Biospecimen, Biostatistics and Medical Informatics, Immune Monitoring. The Developmental Research Program will support a pathway for continued identification and support of diverse research that could replace or improve current projects, and a Career Development Program will recruit and support candidates committed to training in translational research in ovarian cancer. The Developmental Research Program and the Career Developmental Program will provide a framework to mentor young investigators to develop careers in ovarian cancer translational research, and to fertilize testing of high risk, potentiall paradigm changing projects with translational potential.