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

• 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
• 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

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CD 19蛋白（CART 19）的嵌合抗原受体（CAR）T细胞彻底改变了免疫原性。 治疗各种B细胞恶性肿瘤，在某些类型的恶性肿瘤中完全缓解率高达97%。 晚期白血病这些反应中有许多是持续的，但CAR T细胞的扩增和持久性较差。 输注后和抗原阴性逃逸是治疗失败的常见机制。至关重要 研究在应答患者中驱动成功的CAR T细胞功能的因素。以前的研究表明 在淋巴恶性肿瘤中，持久缓解与特异性T细胞通路的激活有关， 只有一些患者经历治疗水平的CAR T细胞扩增和抗肿瘤活性。期间 上一个奖项期间，我们成功地开发了一个全面的了解T细胞的内在和- 耐药的外在机制以及导致复发的肿瘤细胞内在机制。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 抗性机制，并制定克服抗性和增强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 艺术相关的科学平台，探索一些创新的目标。在目标1中，我们将开展广泛的 分析T细胞受体（TCR）重排、载体拷贝数、通过流式细胞仪分析的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，并建立多组学模型，将相关数据和结果联系起来。在目标2中，我们有 设计了一项高影响力的临床试验，以敲除CD 5，一种非传统的阴性免疫检查点分子 和抗原受体信号传导抑制剂，目的是增加3天的治疗指数， 制造的CART 19细胞用于复发性/难治性B细胞恶性肿瘤。最后，在目标3中，我们将执行 与增强CAR T细胞增殖、持久性和抗肿瘤有关的基因的功能分析 职能是为ALL、CLL和NHL开发“同类最佳”产品。使用结构化的多管齐下的策略， 我们希望改善对基于CAR T细胞的B细胞恶性肿瘤治疗的耐药性，并在临床上取得进展。 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 癌症的过继免疫疗法，并提供新的研究前景，可以转化为改善 治疗其他癌症和自身免疫性疾病。