CAREER: Engineering next-generation chimeric antigen receptors for cancer immunotherapy using phospho-proteomics

职业：利用磷酸蛋白质组学设计用于癌症免疫治疗的下一代嵌合抗原受体

• 批准号: 2145853
• 负责人: Nicholas Graham
• 金额: $ 58.23万
• 依托单位: University of Southern California
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2145853&HistoricalAwards=false
• 关键词: CAREER; Engineering; next; generation; chimeric

The immune system fights cancer as well as infections. Cancer immunotherapy attempts to harness and bolster this capability. One FDA-approved immunotherapy involves modifying white blood cells from the patient to recognize and attack tumor cells. The resulting cells are referred to as CAR-T cells. Understanding CAR-T activity could enable design of improved cancer immunotherapy. Identifying the signaling pathways that enhance tumor killing in CAR-T cells is a primary objective of the project. This research project will integrate a broader educational plan to educate students, teachers, and the public. Multi-year outreach to a local high school will provide hands-on experience to a predominantly Hispanic student population. Chimeric antigen receptors (CARs) are comprised of modular protein domains including intracellular signaling/co-stimulation domains. CAR activation stimulates intracellular phosphorylation cascades that promote the cytotoxic functions of T cells. Phospho-proteomics offers quantitative characterization of protein phosphorylation. The governing hypothesis is that a rigorous and comprehensive investigation of CAR signaling using phospho-proteomics will uncover principles of CAR function. This could enable rational engineering of next-generation CARs. Using CD19 as a model antigen, this project will attempt to expand knowledge of CAR signaling and CAR design criteria. The project will pursue the following scientific objectives: 1) Identify signaling pathways that promote CAR-T cell cytotoxic function; 2) Define CAR signaling pathways that enable resistance to exhaustion; and 3) Develop third-generation CARs with improved cytotoxicity and increased persistence. This research will establish a platform that can be used for engineering analysis of CAR signaling and will provide a general framework for CAR design.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

免疫系统可以对抗癌症和感染。癌症免疫疗法试图利用和加强这种能力。fda批准的一种免疫疗法包括修改患者的白细胞来识别和攻击肿瘤细胞。产生的细胞被称为CAR-T细胞。了解CAR-T的活性可以设计出更好的癌症免疫疗法。确定增强CAR-T细胞中肿瘤杀伤的信号通路是该项目的主要目标。这个研究项目将整合一个更广泛的教育计划来教育学生、教师和公众。对当地高中的多年拓展将为西班牙裔学生提供实践经验。嵌合抗原受体（CARs）由模块化的蛋白质结构域组成，包括细胞内信号/共刺激结构域。CAR激活刺激细胞内磷酸化级联反应，从而促进T细胞的细胞毒性功能。磷酸化蛋白质组学提供了蛋白质磷酸化的定量表征。主要假设是，使用磷酸化蛋白质组学对CAR信号传导进行严格而全面的研究将揭示CAR功能的原理。这将使下一代汽车的合理设计成为可能。使用CD19作为模型抗原，该项目将尝试扩展CAR信号传导和CAR设计标准的知识。该项目将追求以下科学目标：1)确定促进CAR-T细胞细胞毒性功能的信号通路；2)定义能够抵抗衰竭的CAR信号通路；3)开发具有更好的细胞毒性和持久性的第三代car。本研究将建立一个可用于CAR信号工程分析的平台，并将为CAR设计提供一个总体框架。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。