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.

项目概要我的长期职业目标是开发可加速癌症研究的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正的影响。当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来开发新的并改进了针对癌症生物学和免疫工程中新出现的问题的临床解决方案。例子包括用于单细胞传感和免疫监测、胶质母细胞瘤脑肿瘤的芯片实验室系统用于快速癌症诊断和预后的微环境建模，以及用于癌症快速诊断和预后的微机械系统我建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。最近 FDA 批准了针对 B 细胞的嵌合抗原受体 (CAR) T 细胞免疫疗法 CAR T 细胞疗法是治疗复发性和难治性白血病以及然而，在许多临床试验中，CAR-T 免疫疗法的临床益处差异很大。复发/难治性白血病试验中报告的总体患者反应仍然是不利的因素。 CAR T 细胞制造等早期步骤可能会导致不同的临床反应治疗、CAR T 细胞耗竭和白血病生态位中的免疫抵抗，但关键要素导致 CAR T 细胞功效变化的原因尚不完全清楚。我们研究的目标是开发新颖的工程系统来探测和分析 CAR T 细胞的免疫学和生物力学属性，并绘制白血病 BM 生态位图以推进目前的 CAR T 细胞免疫疗法首先，我们的目标是重建一种新型的器官型白血病 BM。免疫生态位离体模型剖析不同B-免疫抑制机制的异质性 ALL亚型和临床前评估和优化CD19 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，以便提供可靠且准确的筛选来表征功能最后，我们将探讨调节 CAR T 细胞的机械敏感机制。基于 CAR T 细胞的新见解，提高 CAR T 细胞功效的细胞激活和杀伤过程。机械生物学，我们的目标是设计一个远程“机械开关”，并结合一个“机械启动子”来有效控制CAR T细胞活化和细胞毒性，提高CAR T细胞免疫治疗效果总而言之，我们提出了一个创新框架来精确绘制时空免疫学和安全性。 CAR T细胞激活和杀伤过程中的生物力学动力学，旨在构建离体白血病BM生态位和 CAR T 细胞的机械特征，最终优化 CAR T 细胞的管理、安全性和功效。

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