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

基本信息

批准号：
10657478
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
项目类别：
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/10657478
关键词：
3-Dimensional Acceleration 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 Chip Malignant Bone Marrow Neoplasm Maps Mechanics Modeling Molecular Patients Process Refractory Relapse Reporting Research Safety Site Solid Neoplasm System T-Cell Activation Technology Variant Work anticancer research cancer diagnosis career chimeric antigen receptor chimeric antigen receptor T cells cytotoxicity exhaustion functional status immune resistance immunoengineering improved innovation insight leukemia manufacture microsystems novel patient response patient screening pre-clinical promoter response screening spatiotemporal stem translational cancer research tumor microenvironment

项目摘要

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开发可以加速癌症研究的转化技术从台式机到诊所的发现，对临床试验和患者管理产生真正的影响。我的当前的研究利用了生物材料，微系统和生物制造的工程进步并改善了癌症生物学和免疫工程新兴问题的临床解决方案。具体的示例包括用于单细胞感应和免疫监测的实验室芯片系统，胶质母细胞瘤脑肿瘤用于快速癌症诊断和预后的微环境建模以及微机械系统探索茎和免疫球机制。我提议以新的能力扩展我的工作用于现场免疫治疗患者筛查的新型工程系统的转化癌症研究。随着FDA最近批准B细胞的嵌合抗原受体（CAR）T细胞免疫疗法恶性，汽车T细胞疗法是治愈继电器和难治性白血病的有前途的策略实体瘤。但是，在许多临床试验中，CAR-T免疫疗法的临床益处差异很大继电器/难治性白血病试验中报告的总体患者反应仍然不利。因素可能会造成可变临床反应的贡献，例如汽车T细胞制造或在白血病利基市场中给药，汽车T细胞耗尽和免疫耐药性，但是关键要素导致汽车T细胞效率的变化尚不完全了解。我们研究的目的是开发新型的工程系统，以探测和分析汽车T细胞的免疫和生物力学属性，并映射白血病BM利基市场当前的汽车T细胞免疫疗法。首先，我们旨在重建一种新型的有机白血病BM 免疫利基离体模型剖析了不同B-的免疫抑制机制的异质性所有亚型和临时评估和优化CD19 CAR T细胞免疫疗法有效性的有效性。其次，我们旨在在单细胞水平和/或在3D有机设置中，以提供可靠，准确的筛选以表征功能汽车T细胞的状态。最后，我们将探索调节汽车T-的汽车T细胞机制细胞激活和杀戮过程，以提高汽车T细胞效率。根据汽车T细胞的新见解机械生物学，我们旨在设计一个远程“机械开关”，并将“机械启动器”结合到有效控制汽车T细胞激活和细胞毒性，以改善CAR T细胞免疫疗法的有效性和安全。总之，我们提出了一个创新的框架，以精确绘制时空免疫学和汽车T细胞激活和杀戮过程中的生物力学动力学，旨在构建体内白血病BM利基市场汽车T细胞的机械特征，最终优化了T细胞给药，安全性和效率。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The cellular mechanobiology of aging: from biology to mechanics.

DOI：
10.1111/nyas.14529
发表时间：
2021-05
期刊：
Annals of the New York Academy of Sciences
影响因子：
5.2
作者：
Bajpai A;Li R;Chen W
通讯作者：
Chen W

Probing Single-Cell Mechanical Allostasis Using Ultrasound Tweezers

使用超声镊子探测单细胞机械动态平衡

DOI：
10.1007/s12195-019-00578-z
发表时间：
2019
期刊：
Cellular and Molecular Bioengineering
影响因子：
2.8
作者：
Qian, Weiyi;Chen, Weiqiang
通讯作者：
Chen, Weiqiang

Spatiotemporal dissection of tumor microenvironment via in situ sensing and monitoring in tumor-on-a-chip

DOI：
10.1016/j.bios.2023.115064
发表时间：
2023-01-19
期刊：
BIOSENSORS & BIOELECTRONICS
影响因子：
12.6
作者：
Zhou，Lang;Liu，Lunan;Chen，Pengyu
通讯作者：
Chen，Pengyu

Microskeletal stiffness promotes aortic aneurysm by sustaining pathological vascular smooth muscle cell mechanosensation via Piezo1.

DOI：
10.1038/s41467-021-27874-5
发表时间：
2022-01-26
期刊：
Nature communications
影响因子：
16.6
作者：
Qian W;Hadi T;Silvestro M;Ma X;Rivera CF;Bajpai A;Li R;Zhang Z;Qu H;Tellaoui RS;Corsica A;Zias AL;Garg K;Maldonado T;Ramkhelawon B;Chen W
通讯作者：
Chen W

A Computational Model of Cytokine Release Syndrome during CAR T‐Cell Therapy

CAR T 细胞治疗过程中细胞因子释放综合征的计算模型