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Protein Recognition in Signal Transduction

信号转导中的蛋白质识别

基本信息

批准号：
10460232
负责人：
WENDELL A LIM
金额：
$ 33.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10460232
关键词：
Affinity Antibodies Antigen Targeting Antigens B-Lymphocytes Bar Codes Biochemical Cell Density Cell Line Cells Complex Detection Disease Engineering Epidermal Growth Factor Receptor Grant Immune Immune signaling Lead Libraries Logic Malignant Neoplasms Memory Methods Mus Proteins Series Signal Pathway Signal Transduction Solid Neoplasm T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Agents Tissues Variant Xenograft procedure anti-cancer base behavioral response cancer cell cancer immunotherapy cell killing chimeric antigen receptor chimeric antigen receptor T cells combinatorial density design effective therapy engineered T cells extracellular human tissue improved in vitro testing in vivo in vivo evaluation member mouse model neoplastic cell next generation novel novel therapeutics overexpression receptor response screening

项目摘要

Project Summary/Abstract T cells engineered to recognize and kill cancer cells via chimeric antigen receptors (CARs) have emerged as a promising and potentially transformative therapeutic platform. CAR T cells have proven to be an extremely effective therapy for certain B cell cancers. Nonetheless, many issues still remain in order to apply engineered T cells to a broader range of cancers. First, current CAR T cells, are not able to discriminate between high and low antigen expressing cells. Therefore, targeting antigens that are overexpressed in solid tumor cells (e.g. Her2 or EGFR) can result in lethal off-target killing of bystander tissues expressing lower levels of the antigen. Here we propose to attack this problem by using common biochemical mechanisms for cooperative recognition (i.e. sigmoidal thresholds) to engineer new synthetic T cell receptors or circuits that can sense antigen density. Second, we would ideally like to develop T cell receptor variants that, when activated, drive the cell to a more persistent and effective state (e.g. Th1 or central memory state). To identify next-generation CARs that drive particular T cell responses, we have developed a new strategy for constructing and screening a combinatorial barcoded library of CARs that contain synthetic intracellular co-stimulatory signaling domains. We will screen this library for CAR variants that improve T cell activation, proliferation, and differentiation. We will also use the composite information from analyzing the library to identify critical signaling motifs most responsible for directing T cell response trajectories towards specific paths. Our specific aims are: Aim 1. Engineer synthetic T cell receptors and circuits that can discriminate cancer and bystander cells based on differences in antigen density (using Her2 antigen as a primary testcase) A. Engineer and test a series of cooperative low affinity but high valency CARs for Her2 B. Engineer and test cooperative two-step multi-receptor circuits for sharp threshold detection of Her2 C. Extend these density sensing strategies to sense EGFR density Cells will be tested against cell lines expressing different antigen densities; They will be evaluated in vivo using cell lines and PDX mouse models; crossreactivity will be tested using human tissue xenografts. Aim 2. Build and screen combinatorial CAR libraries to identify synthetic T cell receptors with optimized activation, proliferation and cell fate differentiation A. Develop a novel method for assembling barcoded library of synthetic T cell receptors containing combinations of linear immune signaling motifs (i.e. “synthetic co-stimulatory domains”) B. Screen receptor libraries for receptors with specific optimized or novel response behaviors We will evaluate the therapeutic function of new receptor candidates that emerge from these libraries; Composite analysis will be used to better understand the dominant signaling motifs that direct particular types responses. This project should yield improved next-generation therapeutic T cells.

项目总结/文摘