Novel Immunomodulation and Facilitation of “Suppression Proof” CAR NK cell against Ewing sarcoma

新型免疫调节和促进“抑制证明”CAR NK 细胞对抗尤文肉瘤

• 批准号: 10834579
• 负责人: TIMOTHY P CRIPE
• 金额: $ 25.37万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10834579
• 关键词: Address; Adoptive Immunotherapy; Adoptive Transfer; Adult; Antigens; Binding; Biological Products; Cancer Burden; Cancer Model; Case Study; Cell surface; Cells; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Trials; Combination immunotherapy; Complement; Cytometry; Data; Data Set; Development; Drug Modulation; Effectiveness; Ewings sarcoma; Funding; Future; Genomic approach; Genomics; Goals; Homing; Hybrids; Immune; Immune response; Immunologic Adjuvants; Immunologic Monitoring; Immunotherapy; Inflammatory; Innate Immune Response; Interruption; Knowledge; Macrophage; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Minnesota; Modality; Mutation; Myeloid-derived suppressor cells; Natural Immunity; Natural Killer Cells; New York; Normal Cell; Ohio; Oncolytic viruses; Patients; Pediatric Hospitals; Physicians; Pre-Clinical Model; Proteins; Regimen; Research Personnel; Resistance; Resource Sharing; STAT3 gene; Scientist; Signal Transduction; Site; Solid Neoplasm; Source; T cell response; Technology; Testing; Therapeutic; Traction; Transforming Growth Factor beta; Tumor Immunity; Universities; Virotherapy; Virus; Virus Diseases; adaptive immunity; anti-tumor immune response; cancer cell; cancer immunotherapeutics; cancer immunotherapy; chemokine; chemoradiation; chimeric antigen receptor; chimeric antigen receptor T cells; combinatorial; conventional therapy; cytokine; data integration; effective therapy; embryo/fetus antigen; experience; immune cell checkpoints; immunogenicity; immunoregulation; immunotherapy clinical trials; improved; innate immune mechanisms; medical schools; neoantigens; novel; oncolytic virotherapy; pharmacologic; pre-clinical; rational design; resistance mechanism; response; small molecule; success; synergism; trafficking; transcriptomics; translational study; tumor; tumor microenvironment; 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

总体中心摘要 此应用程序描述了儿科俄亥俄-纽约癌症 (Peds-ONC) 免疫治疗中心，该中心创建于 对 RFA 的响应是儿科免疫疗法发现和开发的第二个巢穴 联盟（PI-DDN）。为了补充 PI-DDN 资助的 U54（Maris 和 Mackall，MPI）， 我们建议，寻求利用适应性免疫进一步开发针对新发现抗原的 CAR-T 细胞 利用先天免疫来针对儿科癌症，规避对传统疗法的耐药性，并 进一步实现适应性/混合免疫方法。 我们的目标是 (1) 识别并克服利用 NK 和 CAR-NK 细胞作为癌症疗法的障碍，(2) 打破对“自身”癌症相关蛋白的耐受性，以及（3）通过靶向抑制来增强免疫治疗 骨髓细胞。我们将通过位于俄亥俄州两个主要基地的四个项目来实现我们的目标 （全国儿童医院）和纽约（纽约医学院）在哥伦布（The 俄亥俄州立大学）和明尼阿波利斯大学（明尼苏达大学）。除了管理共享之外 资源（核心 A，由 Timothy Cripe 博士和副主任 Mitchell Cairo 博士指导），项目是 由综合基因组学和免疫监测共享资源（核心 B，指导）提供科学支持 由 Elaine Mardis 博士和几位专科助理主任负责）。核心 B 通过状态提供集成数据集 最先进的技术，包括质谱流式分析、单细胞转录组学和一系列其他基因组学 能够详细表征和跟踪癌细胞免疫原性、肿瘤免疫的方法 微环境和免疫反应。我们还聚集了强大的外部和内部科学 由知名领导者组成的顾问委员会，其专业知识涵盖项目和共享资源。项目 高度集成和交叉信息。我们建议结合各种方式的治疗方案将 产生协同作用，在临床前儿科癌症模型中驱动抗肿瘤免疫反应，克服 低突变负担的局限性。我们的目标是生成足够的、具有说服力的知识体系 数据为未来临床试验的合理设计提供信息，从而改善癌症儿童的生活。 1