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

• 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
• 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

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 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。很遗憾， 由于CAR T细胞功能不理想、长期 持续的 B 细胞再生障碍性贫血并伴有细胞因子释放综合征 (CRS)。改善治疗和预防 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 白血病骨髓免疫的后续功能反应。这种时空监测技术 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 状况。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 细胞和免疫细胞通讯。为了满足这一需求，本次会议的核心目标 建议开发新型集成“纳米等离子体尺”为基础的纳米传感技术，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 和骨髓免疫抑制细胞。这项技术的成功将首次允许直接 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 就地、实时可追溯。拟议的平台将提供详细且随时间变化的 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。