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

基本信息

批准号：
10676212
负责人：
Nathan Singh
金额：
$ 23.81万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10676212
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 Ligands Ligation Light Lymphoma cell Malignant Neoplasms Mediating Membrane Proteins Memory Memory impairment Mentors Mentorship Molecular Molecular Biology Molecular Immunology Molecular Profiling Non-Hodgkin&apos s Lymphoma Oncology Outcome PIK3CG gene Pathway interactions Patient-Focused Outcomes Patients Pennsylvania Physicians Positioning Attribute Proteins Proteomics Proto-Oncogene Proteins c-akt Receptor Activation 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 Titrations Toxin Training Training Programs Tumor Escape Tumor Immunity Universities Vocational Guidance Work Xenograft Model Xenograft procedure cancer immunotherapy cancer therapy career chemotherapy chimeric antigen receptor chimeric antigen receptor T cells clinical practice curative treatments cytotoxicity design engineered T cells genome editing genome-wide hematopoietic cell transplantation human model improved improved outcome in vivo inhibitor 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 translational immunology tumor

项目摘要

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定义嵌合抗原受体（CAR）T-的分子调节剂针对癌症的细胞活性。鉴于其在治疗方面的效率，汽车疗法产生了极大的热情在B细胞肿瘤中，有重大的限制仍然阻止了其更广泛的成功。大约½的非霍奇金淋巴瘤的患者反应不反应，反映了细胞毒性的衰竭，许多患者由于汽车T细胞持久性失败，治疗后急性淋巴细胞白血病继电器。这研究提出的旨在确定在CAR T细胞中如何调节这些基本T细胞功能。初步数据表明，死亡受体，启动凋亡的表面蛋白在CAR T-中至关重要细胞细胞毒性。使用Penn Car的T细胞和肿瘤样品的分子分析和基因编辑临床试验，我将定义死亡受体在汽车驱动的细胞毒性和肿瘤逃生中的机械作用。持久性是由免疫记忆的形成介导的，数据表明汽车激活了细胞抑制内存形成的程序。该提案中概述的研究将利用异种移植小鼠人类白血病模型以确定PI3K信号通路的汽车激活如何阻碍形成记忆细胞并损害汽车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确定使用蛋白质组学和磷酸蛋白质组学分析限制持久性的其他分子途径。拟议的五年培训计划的目标是我独立研究生涯的发展作为一种身体科学家，专注于细胞免疫疗法。我完成了内部居住培训在我的血液学/肿瘤学研究金培训的最后一年中，医学和AM。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，以及同种异体方面的临床专业知识造血细胞移植。我在不久的将来的目标是发展推动必要的技能独特的科学研究计划。具体来说，我试图获得基因组编辑方面的专业知识，通过教学和实用培训，蛋白质组学和计算生物学，以增强我的科学技能并建立独立性。我的长期目标是提高T细胞免疫疗法的效率和我将由国际的卡尔·六月博士修改细胞免疫疗法的领导者能够为我提供成功的精神训练。为了在我的科学和职业指导中增加广度和深度，我组建了一个指导委员会由杰出科学家组成。宾夕法尼亚大学领导了细胞免疫疗法领域科学和临床实践，为我作为细胞疗法研究者的培训提供了理想的环境。拟议的研究有可能对CAR生物学进行批判性见解。应用询问临床试验样本并剖析限制汽车活动的机制的尖端技术将确定可以预测成功并直接告知更有效的汽车疗法的功能。