Dissecting and engineering CAR T-cell function for optimized Immunotherapy

剖析和设计 CAR T 细胞功能以优化免疫治疗

• 批准号: 10451526
• 负责人: Weiqiang Chen
• 金额: $ 34.27万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451526
• 关键词: 3-Dimensional; B lymphoid malignancy; B-Cell Acute Lymphoblastic Leukemia; Biocompatible Materials; Biomanufacturing; Biomechanics; Bone Marrow; Brain Glioblastoma; CAR T cell therapy; CD19 gene; Cancer Biology; Cancer Prognosis; Cell physiology; Cells; Child; Childhood Precursor B Lymphoblastic Leukemia; Clinic; Clinical; Clinical Trials; Development; Elements; Engineering; Goals; Heterogeneity; Immune; Immunity; Immunologic Monitoring; Immunologics; Immunophenotyping; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Lab-On-A-Chips; Malignant Bone Neoplasm; Maps; Mechanics; Modeling; Molecular; Patients; Process; Refractory; Relapse; Reporting; Research; Safety; Site; Solid Neoplasm; System; T-Cell Activation; Technology; Variant; Work; anticancer research; base; cancer diagnosis; career; chimeric antigen receptor; chimeric antigen receptor T cells; cytotoxicity; exhaustion; functional status; immune resistance; immunoengineering; improved; innovation; insight; leukemia; microsystems; novel; patient response; patient screening; pre-clinical; promoter; response; screening; spatiotemporal; stem; translational cancer research; tumor microenvironment

PROJECT SUMMARY My long-term career goal is to develop translational technologies for cancer research that can accelerate discoveries from the benchtop to the clinic to make a real impact on clinical trials and patient management. My current research leverages engineering advances in biomaterials, microsystems, and biomanufacturing for new and improved clinical solutions to emerging problems in cancer biology and immune engineering. Specific examples include lab-on-a-chip systems for single-cell sensing and immunomonitoring, glioblastoma brain tumor microenvironment modeling for rapid cancer diagnosis and prognosis, and micromechanical systems for exploring stem and immune cell mechanobiology. I proposes to expand on my work in new capacity in translational cancer research for novel engineering systems for on-site immunotherapeutic patient screening. With the recent FDA approval of chimeric antigen receptor (CAR) T-cell immunotherapies for B-cell malignancies, CAR T-cell therapies are a promising strategy to cure relapsed and refractory leukemia as well as solid tumors. However, the clinical benefit of CAR-T immunotherapy varies tremendously in many clinical trials and overall patient responses reported in trials of relapsed/refractory leukemia remain unfavorable. Factors that contribute to variable clinical responses may arise from early steps like CAR T-cell manufacturing or administration, CAR T-cell exhaustion and immunological resistance in the leukemic niche, but the key elements leading to variations in CAR T-cell efficacy are not fully understood. The objective of our research is to develop novel engineering systems to probe and analyze both the immunological and biomechanical attributes of CAR T-cells and map the leukemic BM niche for advancing current CAR T-cell immunotherapies. First of all, we aim to reconstruct a novel organotypic leukemic BM immunity niche ex vivo model to dissect the heterogeneity of immunosuppression mechanisms of different B- ALL subtypes and pre-clinically evaluate and optimize CD19 CAR T-cell immunotherapy efficacy. Secondly, we aim to develop and integrate in situ cellular and molecular immunophenotyping systems at single-cell level and/or in a 3D organotypic setting so as to provide a reliable and accurate screening to characterize the functional status of CAR T-cells. Lastly, we will explore CAR T-cell mechanosensitive mechanisms that regulate CAR T- cell activation and killing process to improve the CAR T-cell efficacy. Based on the new insights from CAR T-cell mechanobiology, we aim to engineer a remote “mechanical switch” and incorporate a “mechanical promoter” to effectively control CAR T-cell activation and cytotoxicity for improved CAR T-cell immunotherapy efficacy and safety. Altogether, we propose an innovative framework to precisely map the spatiotemporal immunological and biomechanical dynamics during CAR T-cell activation and killing, aiming to construct ex vivo leukemic BM niche and mechanical signature of CAR T-cells, ultimately optimize CAR T-cell administration, safety, and efficacy.

项目摘要 我的长期职业目标是为癌症研究开发转化技术， 从实验室到临床的发现，对临床试验和患者管理产生真实的影响。我 目前的研究利用生物材料、微系统和生物制造方面的工程进展， 以及针对癌症生物学和免疫工程中出现的问题的改进的临床解决方案。具体 例子包括用于单细胞传感和免疫监测的芯片实验室系统、胶质母细胞瘤脑肿瘤 用于癌症快速诊断和预后的微环境建模，以及用于 探索干细胞和免疫细胞机械生物学。我提议在新的职位上扩大我的工作， 转译癌症研究的新工程系统的现场免疫患者筛选。 随着最近FDA批准嵌合抗原受体（CAR）T细胞免疫疗法用于B细胞免疫， 对于恶性肿瘤，CAR T细胞疗法是治愈复发性和难治性白血病以及 实体瘤然而，在许多临床试验中，CAR-T免疫疗法的临床获益差异很大 并且在复发性/难治性白血病的试验中报道的总体患者反应仍然是不利的。的因素 导致可变临床反应的原因可能来自早期步骤，如CAR T细胞制造或 在白血病生态位中，CAR T细胞耗竭和免疫抵抗是治疗白血病的关键因素， 导致CAR T细胞功效变化的原因尚未完全了解。 我们研究的目标是开发新的工程系统，以探测和分析 CAR T细胞的免疫学和生物力学属性并绘制白血病BM生态位以促进进展 目前的CAR T细胞免疫疗法。首先，我们的目标是重建一个新的器官型白血病BM 免疫生态位离体模型来剖析不同B- ALL亚型和临床前评估和优化CD 19 CAR T细胞免疫治疗的疗效。其次我们 旨在开发和整合单细胞水平的原位细胞和分子免疫表型系统和/或 在3D器官型设置中，以便提供可靠和准确的筛选来表征功能性 CAR T细胞的状态。最后，我们将探索调节CAR T细胞的机械敏感机制。 细胞活化和杀伤过程，以提高CAR T细胞功效。基于CAR T细胞的新见解 机械生物学，我们的目标是设计一个远程“机械开关”，并纳入“机械启动子”， 有效地控制CAR T细胞活化和细胞毒性以提高CAR T细胞免疫治疗功效， 安全为代价的总之，我们提出了一个创新的框架，以精确地映射时空免疫和 CAR T细胞活化和杀伤期间的生物力学动力学，旨在构建离体白血病BM小生境 以及CAR T细胞的机械特征，最终优化CAR T细胞的施用、安全性和功效。