Modeling based design of chimeric antigen receptors for Natural Killer cell-based immunotherapy

用于基于自然杀伤细胞的免疫治疗的嵌合抗原受体的基于建模的设计

基本信息

批准号：
10701754
负责人：
Stacey Deleria Finley
金额：
$ 51.38万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10701754
关键词：
Activated Natural Killer Cell Antigens B-Lymphocytes Cell Maturation Cell physiology Cell-Mediated Cytolysis Cells Cellular biology Complex Computer Models Data Data Set Development Disease Effector Cell Engineering Equilibrium Flow Cytometry Host Defense Human Immune Immunotherapy Kinetics Knowledge Libraries Ligands Link Machine Learning Mass Spectrum Analysis Mathematics Measures Mediating Membrane Methods Modeling Molecular Multiple Myeloma NK Cell Activation Natural Killer Cell Immunotherapy Natural Killer Cells Outcome Pathway interactions Phosphorylation Play Protein Engineering Receptor Cell Receptor Signaling Research Role Signal Pathway Signal Transduction Signaling Protein Site Source Structure Systems Biology T-Lymphocyte Testing Time Tumor Antigens Western Blotting Work cancer cell cancer immunotherapy cell killing cell type chimeric antigen receptor cytokine cytotoxic cytotoxicity data-driven model design engineered T cells experience immune function in vitro testing in vivo insight interest mathematical model mouse model novel phosphoproteomics predictive modeling receptor receptor-mediated signaling response success tool tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense. The activation of NK cells is mediated by receptor-ligand interactions and downstream intracellular signaling path- ways. One type of immunotherapy that has achieved great success in recent years is based on chimeric antigen receptors (CARs). These are engineered receptors composed of both target recognition and cell activation func- tions that can direct immune cells to mediate killing of cancer cells. Although T cells are the predominant immune cell type used for CAR-based immunotherapy, NK cells provide significant advantages over CAR-engineered T cells because they can be derived from non-autologous sources. However, most studies testing CAR-NK cells have used CAR constructs based on T cell signaling pathways that are not optimized for NK cell signaling. In addition, the development of CAR constructs is largely achieved using a trial-and-error experimental approach, and there is no systematic understanding of how altering the CAR signaling domains influences cell activation. The main objective of this proposal is to identify effective NK based-CAR designs using systems biology tools. Our approach combines computational modeling and quantitative phospho-proteomics to generate a de- tailed understanding of CAR-mediated NK cell signaling and cytotoxicity. The outcome of our work will be a set of validated NK CARs that target and kill BCMA-positive multiple myeloma (MM) cancer cells. We will also test the optimized CARs against CS1-expressing MM cells. The approach builds on our team’s extensive experience in modeling and characterizing cell signaling and studying NK cell biology. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) Characterize intracellular and cellular-level responses of CAR- expressing NK cells; (2) Develop computational models to predict the dynamic responses of CAR-expressing NK cells; (3) Identify novel CAR constructs that effectively activate NK cells. Collectively, our proposed research will generate a quantitative understanding of how CAR signaling encodes NK cell-mediated cytotoxicity and how NK-CAR constructs can be optimized for cancer immunotherapy. Our research will broadly impact the field of cancer immunotherapy by providing insight into how intracellular NK cell signaling and CAR structure influence NK cell activation. Ultimately, this research will expand our knowledge of NK cell signaling and the design criteria for NK-CAR-based immunotherapy for other tumor types and cancer antigens. Our work has the potential to unlock the transformative power of NK-CAR cells for cancer immuno- therapy.

项目摘要/摘要天然杀手（NK）细胞是先天免疫效应细胞，在宿主防御中起着直接作用。这 NK细胞的激活是由接收器配体相互作用和下游细胞内信号通路介导的方式。近年来取得巨大成功的一种免疫疗法是基于嵌合抗原受体（汽车）。这些是由靶标识别和细胞激活功能组成的工程受体可以指导免疫细胞介导癌细胞杀死的情况。尽管T细胞是主要的免疫 NK细胞用于基于汽车的免疫疗法的细胞类型，与汽车工程T具有显着优势细胞是因为它们可以源自非自动源。但是，大多数研究测试CAR-NK细胞使用了基于未针对NK细胞信号的T细胞信号通路的使用CAR构造。在此外，使用反复试验的实验方法可以在很大程度上实现汽车构造的发展，并且对改变汽车信号域如何影响细胞激活没有系统的了解。该提案的主要目的是使用系统生物学确定有效的基于NK的汽车设计工具。我们的方法结合了计算建模和定量磷酸化 - 蛋白质组学，以产生DE- 对CAR介导的NK细胞信号传导和细胞毒性的尾部理解。我们工作的结果将是一套靶向和杀死BCMA阳性多发性骨髓瘤（MM）癌细胞的经过验证的NK汽车。我们还将测试针对表达CS1的MM细胞的优化汽车。该方法基于我们团队的丰富经验在建模和表征细胞信号传导和研究NK细胞生物学方面。在强大的初步数据的指导下，我们建议购买三个具体目标：（1）表征CAR-的细胞内和细胞级反应表达NK细胞；（2）开发计算模型以预测表达汽车的动态响应 NK细胞；（3）确定有效激活NK细胞的新型汽车构建体。总的来说，我们提出的研究将产生对汽车信号如何编码的定量理解 NK细胞介导的细胞毒性以及如何对NK-CAR构建体进行优化用于癌症免疫疗法。我们的研究将通过洞悉细胞内NK细胞，从而广泛影响癌症免疫疗法领域信号传导和汽车结构会影响NK细胞的激活。最终，这项研究将扩大我们对 NK细胞信号传导和针对其他肿瘤类型和癌症的基于NK-CAR的免疫疗法的设计标准抗原。我们的工作有可能释放NK-CAR细胞对癌症免疫的变化能力治疗。