Mechanisms regulating chimeric antigen receptor T-cell activity in cancer

癌症中嵌合抗原受体 T 细胞活性的调节机制

• 批准号: 10224678
• 负责人: Nathan Singh
• 金额: $ 23.81万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224678
• 关键词: AKT inhibition; Acute Lymphocytic Leukemia; Aftercare; Allogenic; Antibodies; Antigens; Apoptosis; B-Cell Neoplasm; Biological; Biological Markers; Biology; CD19 Antigens; CD19 gene; CD95 Antigens; Cell Surface Proteins; Cell Therapy; Cell physiology; Cells; Cellular immunotherapy; Cessation of life; Chemicals; Clinical; Clinical Trials; Computational Biology; Cytotoxin; Data; Defect; Development; Ectopic Expression; Environment; Failure; Fellowship; Foundations; Future; Genes; Genetic; Goals; Hematologic Neoplasms; Hematology; Hematopoietic Neoplasms; Hybrids; Immunologic Memory; Immunologist; Immunology; Immunotherapy; Impairment; In Vitro; Innovative Therapy; Internal Medicine; International; Investigation; Knock-out; Knowledge; Lead; Ligands; Ligation; Light; Lymphoma cell; Malignant Neoplasms; Mediating; Membrane Proteins; Memory; Memory impairment; Mentors; Mentorship; Molecular; Molecular Biology; Molecular Immunology; Molecular Profiling; Non-Hodgkin' s Lymphoma; Oncology; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Pennsylvania; Physicians; Positioning Attribute; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Cell; Receptor Signaling; Research; Research Personnel; Residencies; Resistance; Role; Sampling; Science; Scientist; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Surface; T cell regulation; T memory cell; T-Cell Receptor; T-Lymphocyte; TNFSF10 gene; Techniques; Toxin; Training; Training Programs; Tumor Escape; Tumor Immunity; Universities; Vocational Guidance; Work; Xenograft Model; Xenograft procedure; base; cancer immunotherapy; cancer therapy; career; chemotherapy; chimeric antigen receptor; chimeric antigen receptor T cells; clinical practice; cohesion; curative treatments; cytotoxicity; design; engineered T cells; genome editing; genome-wide; hematopoietic cell transplantation; human model; improved; improved outcome; in vivo; inhibitor/antagonist; insight; knockout gene; leukemia; leukemia relapse; leukemia/lymphoma; mouse model; neoplastic cell; novel; perforin; phosphoproteomics; predictive signature; prevent; programs; receptor; receptor expression; research clinical testing; responders and non-responders; response; skills; success; tumor

PROJECT SUMMARY The proposed research focuses on defining the molecular regulators of chimeric antigen receptor (CAR) T- cell activity against cancer. CAR therapy has generated great enthusiasm in light of its efficacy in the treatment of B-cell neoplasms, however significant limitations still prevent its broader success. Approximately ½ of patients with non-Hodgkin lymphoma do not respond, reflecting a failure of cytotoxicity, and many patients with acute lymphoblastic leukemia relapse after treatment due to a failure of CAR T-cell persistence. The studies proposed aim to determine how these essential T-cell functions are regulated in CAR T cells. Preliminary data suggest that death receptors, surface proteins that initiate apoptosis, are essential in CAR T- cell cytotoxicity. Using molecular profiling and gene editing of T-cell and tumor samples from Penn's CAR clinical trials, I will define the mechanistic role of death receptors in CAR-driven cytotoxicity and tumor escape. Persistence is mediated by the formation of immune memory, and data show that CARs activate cellular programs that suppress memory formation. The studies outlined in this proposal will utilize xenograft mouse models of human leukemia to determine how CAR activation of the PI3K signaling pathway impedes formation of memory cells and impairs CAR T-cell persistence. Using clinical trial samples, this work will further aim to identify additional molecular pathways that limit persistence using proteomic and phosphoproteomic analysis. The goal of the proposed five-year training program is the development of my independent research career as a physician-scientist focused on cellular immunotherapies. I completed residency training in Internal Medicine and am in my final year of fellowship training in Hematology/Oncology. I am now expanding my scientific expertise in molecular biology and immunology, as well as clinical expertise in allogeneic hematopoietic cell transplantation. My goal for the near future is to develop the skills necessary to drive a distinctive program of scientific investigation. Specifically, I seek to gain expertise in genome editing, proteomics and computational biology through didactic and practical training in order to augment my scientific skillset and establish independence. My long-term goal is to enhance the efficacy of T-cell immunotherapy and improve outcomes for patients with hematologic cancers. I will be mentored by Dr. Carl June, an international leader in cellular immunotherapy who is well equipped to provide me with the mentorship I need to succeed. To add breadth and depth to my scientific and career guidance, I have assembled a Mentoring Committee composed of exceptional scientists. The University of Pennsylvania had led the field of cellular immunotherapy science and clinical practice, and provides the ideal environment for my training as a cell therapy investigator. The proposed studies have the potential to provide critical insight into CAR biology. The application of cutting-edge techniques to interrogate clinical trial samples and dissect the mechanisms limiting CAR activity will identify features that predict success and directly inform the design of more effective CAR therapies.

项目摘要 拟议的研究重点是确定嵌合抗原受体（CAR）T- 细胞抗癌活性。鉴于其在治疗中的疗效，CAR疗法产生了极大的热情。 B细胞肿瘤，然而，重大的局限性仍然阻止其更广泛的成功。大约一半 非霍奇金淋巴瘤患者没有反应，反映了细胞毒性的失败，许多患者 急性淋巴细胞白血病治疗后复发，由于CAR T细胞持续性失败。的 提出的研究旨在确定这些基本T细胞功能如何在CAR T细胞中调节。 初步数据表明，死亡受体，启动细胞凋亡的表面蛋白，在CAR-T细胞中是必不可少的。 细胞毒性使用来自Penn CAR的T细胞和肿瘤样本的分子分析和基因编辑 在临床试验中，我将定义死亡受体在CAR驱动的细胞毒性和肿瘤逃逸中的机制作用。 持久性是由免疫记忆的形成介导的，数据显示汽车激活细胞免疫记忆。 抑制记忆形成的程序本提案中概述的研究将利用异种移植小鼠 人白血病模型，以确定CAR活化PI 3 K信号通路如何阻碍形成 并损害CAR T细胞的持久性。使用临床试验样本，这项工作将进一步旨在 使用蛋白质组学和磷酸化蛋白质组学分析鉴定限制持久性的其他分子途径。 我所建议的五年培训计划的目标是发展我的独立研究事业 作为一名专注于细胞免疫疗法的医生兼科学家。我在内部完成了住院医师培训 我在血液学/肿瘤学奖学金培训的最后一年。我现在正在扩大我的 分子生物学和免疫学方面的科学专业知识以及同种异体移植的临床专业知识 造血细胞移植我在不久的将来的目标是培养驾驶汽车所需的技能。 独特的科学研究计划。具体来说，我寻求获得基因组编辑方面的专业知识， 蛋白质组学和计算生物学通过教学和实践培训，以增加我的科学 技能和建立独立性。我的长期目标是提高T细胞免疫疗法的疗效， 改善血液系统癌症患者的预后。我将由卡尔·琼博士指导，他是一位国际 他是细胞免疫疗法的领导者，能够为我提供成功所需的指导。 为了增加我的科学和职业指导的广度和深度，我组建了一个指导委员会， 由杰出的科学家组成。宾夕法尼亚大学在细胞免疫疗法领域处于领先地位 科学和临床实践，并提供了理想的环境，我的培训作为一个细胞疗法研究员。 拟议的研究有可能为CAR生物学提供关键的见解。的应用 询问临床试验样品并剖析限制CAR活性的机制的尖端技术 将识别预测成功的特征，并直接为更有效的CAR疗法的设计提供信息。