Roswell Park Ovarian Cancer SPORE

综述-罗斯威尔公园卵巢癌孢子 这是罗斯威尔公园卵巢癌孢子的修订竞争续期申请。我们已经做出了 在每个研究项目的翻译目标和人类终点方面取得重大进展 (IRP)。我们非常成功的发展研究计划(DRP)和职业提升计划(CEP) 催化了新的卵巢癌翻译性研究项目、合作和外部资金 获奖者。我们的总体目标不变：开展多学科、以机制为基础的 协作性翻译研究将对卵巢癌女性患者产生最大可能的影响。 由于免疫疗法在卵巢癌患者中只取得了不大的成功，我们继续 独特地关注通过解开免疫抵抗来产生有效抗肿瘤免疫的新策略 反应机制和识别新的蛋白质基因组生物标记物。经过大量的规划和 由我们的内部和外部咨询委员会以及患者权益倡导委员会提供的指导，我们利用 我们的DRP和CEP非常成功地提出了三个双向转换IRP，以解决基本和 卵巢癌临床研究中的重要问题。新的IRP1和IRP2是由两个 DRP奖和新的IRP3是从CEP奖发展而来的。IRP1将测试一种携带有 CXCR4拮抗剂联合PDL1阻断肿瘤免疫抑制及限制T细胞 一项随机的I/II期临床试验中的疲惫。IRP2将测试呈现NY-ESO-1-反应性的新策略 转TcR基因T细胞对转化生长因子的抑制作用不敏感，同时中和M2- 巨噬细胞/髓系来源的抑制细胞。IRP3提出了一个全新的识别概念 卵巢癌细胞免疫表位与树突状细胞的错配 绕过这种不匹配的计算方法。IRp1从计划中的临床试验开始；阶段 IRP2和IRP3的I/II临床试验将在临床前、启用IND的翻译后的第三年开始 学习。该计划还继续扩大卵巢癌翻译的新途径的机会。 通过其成功的DRP和CEP进行研究。四个高度集成、互联的共享资源核心- 管理学、生物医学与病理学、生物统计学与生物信息学、免疫基因组学 向孢子提供创新的技术和资源，不重复现有的共享资源 在罗斯威尔公园。这项申请得到了近400万美元机构承诺的大力支持，以确保其 成功实施了高度创新的转化研究，改变了临床实践范式 卵巢癌。

Overall Summary – Roswell Park Ovarian Cancer SPORE This is the revised competing renewal application of the Roswell Park Ovarian Cancer SPORE. We have made significant progress on the translational objectives and human endpoints of each Individual Research Project (IRP). Our highly successful Developmental Research Program (DRP) and Career Enhancement Program (CEP) have catalyzed new translational ovarian cancer research projects, collaborations, and extramural funding for awardees. Our overarching goal remains unchanged: to conduct multidisciplinary, mechanism-based and collaborative translational research that will have the highest possible impact for women with ovarian cancer. Because immunotherapies have met with only modest success in ovarian cancer patients, we continue to uniquely focus on novel strategies for generating effective anti-tumor immunity by unraveling immune-resistance mechanisms and identifying novel proteogenomic biomarkers of responsiveness. After significant planning and guidance by our Internal and External Advisory Boards, and Patient Advocate Committee, we have leveraged our highly successful DRP and CEP to propose three bi-directional translational IRPs addressing basic and clinical research questions of importance in ovarian cancer. The new IRP1 and IRP2 evolved as a result of two DRP awards and the new IRP3 developed from a CEP award. IRP1 will test an oncolytic virus armed with a CXCR4 antagonist in combination with PDL1 blockade to abrogate tumor immune suppression and limit T cell exhaustion in a randomized Phase I/II clinical trial. IRP2 will test a novel strategy of rendering NY-ESO-1-reactive TCR transgenic T cells to be insensitive to the suppressive action of TGF and concomitantly neutralize M2- macrophages/myeloid-derived suppressor cells. IRP3 addresses the completely novel concept of identifying mismatch between immunopeptidomes of ovarian cancer cells versus dendritic cells and leveraging a computational approach of bypassing such mismatch. IRP1 commences with a planned clinical trial; the Phase I/II clinical trials in IRP2 and IRP3 will commence in year 3 following preclinical, IND-enabling translational studies. The program also continues to expand opportunities for new avenues of ovarian cancer translational research via its successful DRP and CEP. The four highly integrated, interconnected shared resource cores – Administration, Biospecimen & Pathology, Biostatistics & Bioinformatics, and Immunogenomics – bring innovative technology and resources to the SPORE and do not duplicate pre-existing shared resources available at Roswell Park. This application is strongly supported by nearly $4M institutional commitment to ensure its success of conducting highly innovative translational research that changes the clinical practice paradigm in ovarian cancer.