From the Past to the Future: Chimeric Antigen Receptor T cells for Lymphoid Malignancies

从过去到未来：嵌合抗原受体 T 细胞治疗淋巴恶性肿瘤

基本信息

批准号：
10713200
负责人：
Joseph Anthony Fraietta
金额：
$ 44.22万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713200
关键词：
Ablation Acute Lymphocytic Leukemia Address Adopted Adoptive Immunotherapy Antigen Receptors Antigens Autoimmune Diseases Automobile Driving Award B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Leukemia B-Cell NonHodgkins Lymphoma Biological Assay Biological Markers Biology Blood CAR T cell therapy CBL gene CD19 Antigens CD19 gene CRISPR/Cas technology CTLA4 gene Cell Culture Techniques Cell physiology Cells Characteristics Chemoresistance Chronic Lymphocytic Leukemia Clinic Clinical Clinical Trials Collaborations Critical Pathways Data Development Disease remission Dose Engineering Exhibits Flow Cytometry Future Gene Targeting Genes Genetic Genetic Transcription Goals Hematological Disease Heterogeneity Human Immune Immunologics Immunotherapy Infiltration Infusion procedures Investigation Knock-out Laboratories Lead Libraries Link Lupus Lymphocyte Malignant Lymph Node Neoplasm Malignant Neoplasms Malignant lymphoid neoplasm Mediator Modeling Outcome PRDM1 gene PTPN6 gene Pathway interactions Patients Population Proliferating Property Proteins Public Health Publishing Reagent Receptor Signaling Recurrent disease Refractory Relapse Research Resistance Resolution Safety Sampling Science Series Serum Specific qualifier value Structure T cell therapy T-Cell Development T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Technology Testing Therapeutic Therapeutic Index Time Toxic effect Translating Treatment Failure Tumor Tissue Veins Work Xenograft Model biobank cancer immunotherapy cellular engineering chimeric antigen receptor chimeric antigen receptor T cells clinically actionable cohort cytokine design exhaust experience experimental study first-in-human follow-up genome editing head-to-head comparison immune checkpoint improved improved outcome in vivo inhibitor innovation leukemia manufacture manufacturing process mouse model multiple omics neoplastic cell new technology next generation novel pre-clinical prevent programmed cell death protein 1 refractory cancer resistance mechanism response safety assessment success synthetic biology tool trafficking treatment optimization tumor vector

项目摘要

Summary/Abstract (PROJECT 1) Chimeric antigen receptor (CAR) T cells directed to the CD19 protein (CART19) have revolutionized the treatment of a variety of B cell malignancies, with complete remission rates as high as 97% in certain types of advanced leukemia. Many of these responses are sustained, but poor CAR T cell expansion and persistence following infusion and antigen-negative escape are common mechanisms of treatment failure. It is critical to investigate factors driving successful CAR T cell function in responding patients. Previous studies have indicated that in lymphoid malignancies, durable remission is associated with activation of specific T cell pathways and only some patients experience therapeutic levels of CAR T cell expansion and antitumor activity. During the previous award period, we successfully developed a comprehensive understanding of the T cell-intrinsic and - extrinsic mechanisms of resistance as well as tumor cell-intrinsic mechanisms that lead to relapse. Here we propose extensive next-generation analyses to understand properties of optimal CAR T cell therapy, elucidate mechanisms of resistance, and develop strategies to overcome resistance and enhance CAR T cell activity to cure more patients with hematologic diseases. We will take advantage of already established successful collaborations with core laboratories possessing expertise in cell manufacturing, gene editing, and state-of-the- art correlative science platforms to explore a number of innovative aims. In Aim 1, we will carry out an extensive analysis of T cell receptor (TCR) rearrangements, vector copy number, T cell subsets analyzed by flow cytometry, serum cytokines and biomarkers (~7,000), and transcriptional landscapes of CAR T cells in blood as well as tumor tissues and formulate multi-omics models linking correlative data and outcome. In Aim 2, we have designed a high-impact clinical trial to knockout CD5, an unconventional negative immune checkpoint molecule and inhibitor of antigen-receptor signaling, with the goal of increasing the therapeutic index of 3-day manufactured CART19 cells for relapsed/refractory B-cell malignancies. Finally, in Aim 3, we will carry out functional analyses of genes implicated in potentiating CAR T cell proliferation, persistence, and antitumor function to develop `best-in-class' products for ALL, CLL, and NHL. Using a structured, multi-pronged strategy, we hope to ameliorate resistance to CAR T cell-based therapies for B-cell malignancies and clinically advance several next-generation synthetic biology tools. This work is expected to open therapeutic horizons in the field of adoptive immunotherapy for cancer and offer new research prospects that could be translated to improving the treatment of other cancers and autoimmune disorders.

摘要/摘要（项目 1）针对 CD19 蛋白 (CART19) 的嵌合抗原受体 (CAR) T 细胞彻底改变了治疗多种B细胞恶性肿瘤，某些类型的完全缓解率高达97% 晚期白血病。其中许多反应是持续的，但 CAR T 细胞扩增和持久性较差输注后和抗原阴性逃逸是治疗失败的常见机制。至关重要的是研究驱动 CAR T 细胞在应答患者中成功发挥功能的因素。先前的研究表明在淋巴恶性肿瘤中，持久缓解与特定 T 细胞通路的激活有关只有部分患者的 CAR T 细胞扩增和抗肿瘤活性达到治疗水平。期间在上一个奖项期间，我们成功地对 T 细胞本质有了全面的了解，并且 - 耐药的外在机制以及导致复发的肿瘤细胞内在机制。在这里我们提出广泛的下一代分析，以了解最佳 CAR T 细胞疗法的特性，阐明耐药机制，并制定克服耐药性和增强 CAR T 细胞活性的策略治愈更多血液病患者。我们将利用已经建立的成功与拥有细胞制造、基因编辑和最新技术专业知识的核心实验室合作艺术相关科学平台探索多项创新目标。在目标 1 中，我们将开展广泛的 T 细胞受体 (TCR) 重排分析、载体拷贝数、流式分析 T 细胞亚群细胞计数、血清细胞因子和生物标志物（约 7,000）以及血液中 CAR T 细胞的转录景观以及肿瘤组织并制定连接相关数据和结果的多组学模型。在目标 2 中，我们有设计了一项高影响力的临床试验来敲除 CD5（一种非常规的阴性免疫检查点分子）和抗原受体信号传导抑制剂，目的是提高 3 天的治疗指数制造用于治疗复发/难治性 B 细胞恶性肿瘤的 CART19 细胞。最后，在目标 3 中，我们将执行对增强 CAR T 细胞增殖、持久性和抗肿瘤作用的基因进行功能分析致力于为 ALL、CLL 和 NHL 开发“一流”产品。采用结构化、多管齐下的策略，我们希望改善 B 细胞恶性肿瘤对 CAR T 细胞疗法的耐药性并取得临床进展几种下一代合成生物学工具。这项工作有望打开该领域的治疗视野癌症过继免疫疗法的研究并提供新的研究前景，可以转化为改善其他癌症和自身免疫性疾病的治疗。