Childhood high-risk sarcoma derived human satellite (HSAT) and endogenous retroviral (ERV) RNAs in immunosuppression and inflammation

儿童高危肉瘤衍生人类卫星 (HSAT) 和内源性逆转录病毒 (ERV) RNA 在免疫抑制和炎症中的作用

• 批准号: 10401125
• 负责人: TIMOTHY P CRIPE
• 金额: $ 20.28万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401125
• 关键词: Antigens; Biological; Cancer Burden; Cancer Model; Cells; Childhood; Clinical Trials; Combination immunotherapy; Complement; Cytometry; Data; Data Set; Development; Effectiveness; Funding; Future; Genomic approach; Genomics; Goals; Human; Hybrids; Immune; Immune response; Immunologic Monitoring; Immunosuppression; Immunotherapy; Inflammation; Knowledge; Malignant Childhood Neoplasm; Malignant Neoplasms; Minnesota; Modality; Mutation; Myeloid-derived suppressor cells; Natural Immunity; Natural Killer Cells; New York; Ohio; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Proteins; RNA; Regimen; Resistance; Resource Sharing; Site; Technology; Testing; Therapeutic; Universities; Virus; adaptive immunity; anti-tumor immune response; base; cancer cell; cancer immunotherapy; chimeric antigen receptor T cells; conventional therapy; design; effective therapy; high risk; immunogenicity; immunotherapy clinical trials; improved; medical schools; novel; pre-clinical; response; sarcoma; small molecule; synergism; transcriptomics; tumor-immune system interactions

Overall Center Abstract This application describes the Pediatric Ohio-New York Cancer (Peds-ONC) Immunotherapy Center, created in response to the RFA as a second nidus for the Pediatric Immunotherapy Discovery and Development Consortium (PI-DDN). To complement the funded U54 (Maris and Mackall, MPI) of the PI-DDN that largely seeks to harness adaptive immunity to further develop CAR-T cells against newly identified antigens, we propose to harness innate immunity to target pediatric cancers, to circumvent resistance to conventional therapy, and to further enable adaptive/hybrid immune approaches. Our aims are to (1) Identify and overcome barriers to utilizing NK and CAR-NK cells as cancer therapeutics, (2) break tolerance to “self” cancer-associated proteins and (3) enhance immunotherapies by targeting suppressive myeloid cells. We will accomplish our aims through four projects, based at two major sites based in Ohio (Nationwide Children’s Hospital) and New York (New York Medical College) with subsites in Columbus (The Ohio State University) and Minneapolis (Univeristy of Minnesota). In addition to an Administrative Shared Resource (Core A, directed by Dr. Timothy Cripe and Associate Director Dr. Mitchell Cairo), the projects are scientifically supported by a comprehensive Genomics & Immune Monitoring Shared Resource (Core B, directed by Dr. Elaine Mardis with several subspecialy assistant directors). Core B provides integrated datasets via state- of-the-art technologies including mass cytometry, single cell transcriptomics, and an array of other genomics approaches that enable detailed characterizations and tracking of cancer cell immunogenicity, the tumor immune microenvironment, and immunologic responses. We have also assembled strong external and internal scientific advisory boards of renowned leaders whose expertise spans the projects and shared resources. The projects are highly integrated and cross-informative. We propose that therapeutic regimens that combine modalities will produce synergy that drives anti-tumor immune responses in preclinical pediatric cancer models, overcoming the limitations of low mutational burdens. Our goal is to generate a sufficient body of knowledge with compelling data to inform the rational design of future clinical trials and thereby improve the lives of children with cancer. 1

整体中心摘要 该应用描述了小儿俄亥俄州 - 纽约癌症（PEDS-ONC）免疫疗法中心 对RFA作为小儿免疫疗法发现和发育的第二个Nidus的反应 财团（PI-DDN）。要完成PI-DDN的资助的U54（Maris和MacCall，MPI） 寻求利用适应性免疫学，以进一步开发针对新鉴定的抗原的CAR-T细胞，我们提出 利用先天的免疫力来靶向小儿癌，规避对常规疗法的抵抗力，并 进一步启用适应性/混合免疫方法。 我们的目的是（1）识别并克服使用NK和CAR-NK细胞作为癌症治疗的障碍，（2） 对“自我”与癌症相关蛋白的破损耐受性，（3）通过靶向抑制来增强免疫疗法 髓样细胞。我们将通过基于俄亥俄州的两个主要网站的四个项目来实现目标 （全国儿童医院）和纽约（纽约医学院），在哥伦布（ 俄亥俄州立大学）和明尼阿波利斯（明尼苏达州大学）。除了共享行政 资源（Core A，由Timothy Cripe博士和副主任Mitchell Cairo博士执导），这些项目是 由全面的基因组学和免疫监测共享资源科学支持（核心B，指导 伊莱恩·马迪斯（Elaine Mardis）博士与几位亚科助理董事）。 Core B通过状态提供集成数据集 - ART技术包括质量细胞术，单细胞转录组学和一系列其他基因组学 肿瘤免疫的方法可以使详细特征和跟踪癌细胞免疫原性跟踪 微环境和免疫学反应。我们还组装了强大的外部和内部科学 著名领导者的咨询委员会的专业知识涵盖了项目和共享资源。项目 高度整合和跨信息。我们提出，结合方式的治疗方案将 产生协同作用，可在临床前小儿癌模型中驱动抗肿瘤免疫反应，克服 低突变烧伤的局限性。我们的目标是通过引人注目的是产生足够的知识 数据以告知未来临床试验的合理设计，从而改善了癌症儿童的生活。 1