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

CAR T细胞免疫治疗中MAP-免疫细胞与纳米浆体规则的通讯 针对CD19的嵌合抗原受体(CAR)修饰的基因工程T细胞提供了一种 治疗癌症的创新方法，特别是B细胞急性淋巴细胞白血病(B-ALL)。不幸的是， 这种免疫疗法的实际应用受到CAR T细胞功能不尽如人意的极大阻碍。 持续性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而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的实时和可追踪监测将 从机制上理解CAR T细胞生理病理的启动、激活、沟通和 白血病骨髓免疫中的后续功能反应。这种时空监测技术 在现有的临床实践中严重缺乏，这些实践主要基于“静态”下的测量 条件。因此，出现了对允许直接可视化和绘制细胞因子图的平台的需求 生产、扩散、运输，以更好地了解高度异质的功能多样性 多功能CAR T细胞和免疫细胞通讯。为了满足这一需求，该项目的核心目标是 建议开发基于纳米尺的新型集成纳米传感技术，以解决 单个CD19CAR T细胞分泌细胞因子的时间动态及其与B-ALL细胞的串扰 和骨髓免疫抑制细胞。这项技术的成功将第一次允许直接 在一种高灵敏度、多路、无标记 现场和实时可追溯的方式。拟议的平台将提供详细的和与时间相关的 CAR T细胞对刺激的反应和在临床前抑制生态位中进化的机制 筛选最佳、有效、安全的CAR T细胞疗法。

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.