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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：
10166883
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/10166883
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

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.

项目总结