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细胞免疫治疗中使用纳米等离子体标尺映射白血病免疫细胞通信 用靶向CD 19的嵌合抗原受体（CAR）修饰的遗传工程化T细胞提供了一种免疫调节剂。 用于治疗癌症，特别是B细胞急性淋巴细胞白血病（B-ALL）的创新方法。不幸的是， 这种免疫疗法的实际应用受到不令人满意的CAR T细胞功能、长时间的 持续性B细胞发育不全和伴随的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的和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且可追溯的监测， 能够从机制上理解CAR T细胞在启动、激活、通讯和 随后白血病骨髓免疫功能反应。这种时空监测技术 在现有的临床实践中严重缺乏，这些临床实践主要基于“静态”下的测量。 条件因此，对于允许细胞因子的直接可视化和映射的平台存在新兴的需求。 生产、扩散、运输，以便更好地了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。为了满足这一需求，本组织的核心目标是 建议是开发新的集成的“nanoplamson规则”为基础的纳米传感技术，以解决 单个CD 19 CAR T细胞的细胞因子分泌的时间动力学以及与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 在高灵敏度、多重、无标记、 现场和实时可追溯的方式。拟议的平台将提供一个详细的、有时限的 CAR T细胞如何响应刺激并在临床前抑制性小生境中进化的机制 筛选最佳、有效和安全的CAR T细胞疗法。