Map Leukemia-immune Cell Talks with Nanoplasmon Ruler in CAR T-Cell Immunotherapy

在 CAR T 细胞免疫疗法中使用 Nanoplasmon Ruler 绘制白血病免疫细胞对话图

基本信息

批准号：
10059324
负责人：
Pengyu Chen
金额：
$ 54.41万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10059324
关键词：
Address B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes B-cell precursor acute lymphoblastic leukemia cell Behavior Biosensing Techniques Biosensor Bone Marrow CAR T cell therapy CD19 Antigens CD19 gene Cell Communication Cell physiology Cells Characteristics Clinical Communication Complex Cytokine Network Pathway Development Diffusion Engineering Enzymes Fingerprint Functional disorder Genetic Engineering Hybrids Immune Immune signaling Immunity Immunologics Immunosuppressive Agents Immunotherapy Impairment In Situ Individual Label Leukemic Cell Location Malignant Neoplasms Maps Measurement Methods Microfluidics Monitor Outcome Population Preventive treatment Procedures Production Refractory Relapse Research Resistance Signal Pathway Signal Transduction Suppressor-Effector T-Lymphocytes T cell response T-Cell Activation T-Lymphocyte Techniques Technology Therapeutic Time Transportation Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells Visualization acute T-cell lymphoblastic leukemia cell aptamer base cancer cell cell type chimeric antigen receptor chimeric antigen receptor T cells clinical application clinical practice cytokine cytokine release syndrome cytotoxicity design engineered T cells exhaustion improved individual variation innovation insight leukemia nanoplasmonic nanosensors novel patient response practical application pre-clinical preclinical evaluation programs response screening sensor spatiotemporal success therapy outcome therapy resistant tool tumor microenvironment

项目摘要

Map Leukemia-immune Cell Communication with Nanoplasmon Ruler in CAR T-Cell Immunotherapy Genetically engineered T-cells modified with chimeric antigen receptors (CAR) targeting CD19 provide an innovative method for treating cancer, especially for B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, practical application of this immunotherapy is greatly hindered by the unsatisfactory CAR T-cell function, long- lasting B cell aplasia and accompanied cytokine release syndrome (CRS). Improved therapeutic and preventive treatments require comprehensive understanding of the complex and dynamic cytokine secretion behavior of CAR T-cells and their communication with cancer cells and other immune cells in the tumor microenvironment. More importantly, real-time and traceable monitoring of both the location and timing of cytokine secretion would enable mechanistic understanding of CAR T-cell physiopathology in initiation, activation, communication and subsequent functional responses in leukemic bone marrow immunity. Such spatiotemporal monitoring technique is critically lacking within existing clinical practices, which are primarily based on measurements under “static” conditions. Thus, there is an emerging need for platforms that allow direct visualization and mapping of cytokine production, diffusion, transportation for better understanding the highly heterogeneous functional diversity of polyfunctional CAR T-cells and immune cell communications. To address this need, the central objectives of this proposal are to develop novel integrated `nanoplamson ruler'-based nanosensing technology to resolve the temporal dynamics of cytokine secretion from individual CD19 CAR T-cells and the crosstalk with B-ALL cells and bone marrow immune suppressor cells. The success of this technology will allow, for the first time, the direct visualization of multiplex cytokine secretion from individual CAR T-cell in a high-sensitivity, multiplex, label-free, in situ and real-time traceable manner. The proposed platform would provide a detailed and time-dependent mechanisms of how CAR T-cell response to stimulation and evolve in a suppressive niche for preclinical screening of optimal, effective and safe CAR T-cell therapy.

在 CAR T 细胞免疫疗法中使用 Nanoplasmon Ruler 绘制白血病免疫细胞通讯图用靶向 CD19 的嵌合抗原受体 (CAR) 修饰的基因工程 T 细胞提供了不幸的是，治疗癌症，特别是 B 细胞急性淋巴细胞白血病 (B-ALL) 的创新方法。由于CAR T细胞功能不理想、长期持久的 B 细胞再生障碍性贫血和伴随的细胞因子释放综合征 (CRS) 的治疗和预防得到改善。治疗需要全面了解复杂且动态的细胞因子分泌行为 CAR T 细胞及其与肿瘤微环境中的癌细胞和其他免疫细胞的通讯。更重要的是，对细胞因子分泌的位置和时间进行实时、可追踪的监测将有助于能够从机制上理解 CAR T 细胞的启动、激活、通讯和病理生理学这种时空监测技术的后续功能反应。现有的临床实践中严重缺乏，这些实践主要基于“静态”下的测量因此，迫切需要能够直接可视化和绘制细胞因子图谱的平台。生产、扩散、运输，以更好地理解高度异质的功能多样性多功能 CAR T 细胞和免疫细胞通信是该项目的核心目标。建议开发基于纳米传感技术的新型集成“纳米等离子体尺”，以解决单个 CD19 CAR T 细胞分泌细胞因子的时间动态以及与 B-ALL 细胞的串扰这项技术的成功将首次实现直接免疫抑制细胞。以高灵敏度、多重、无标记的方式可视化单个 CAR T 细胞分泌的多重细胞因子拟议的平台将提供详细且与时间相关的信息。 CAR T 细胞如何响应刺激并在临床前抑制生态位中进化的机制筛选最佳、有效和安全的 CAR T 细胞疗法。