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.

项目概要/摘要自然杀伤 (NK) 细胞是先天免疫效应细胞，在宿主防御中发挥直接作用。 NK 细胞的激活是由受体-配体相互作用和下游细胞内信号通路介导的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（CAR）是由目标识别和细胞激活功能组成的工程受体。尽管T细胞是主要的免疫细胞，但可以引导免疫细胞介导杀死癌细胞。用于基于 CAR 的免疫疗法的细胞类型，NK 细胞比 CAR 工程 T 细胞具有显着优势细胞，因为它们可以来自非自体来源。然而，大多数研究测试 CAR-NK 细胞。使用基于 T 细胞信号传导途径的 CAR 构建体，但未针对 NK 细胞信号传导进行优化。此外，CAR 构建体的开发很大程度上是通过试错实验方法实现的，对于改变 CAR 信号传导域如何影响细胞激活还没有系统的了解。该提案的主要目标是利用系统生物学确定有效的基于 NK 的 CAR 设计我们的方法结合了计算建模和定量磷酸化蛋白质组学来生成反- 对 CAR 介导的 NK 细胞信号传导和细胞毒性的深入了解我们的工作成果将是一系列的。我们还将测试靶向并杀死 BCMA 阳性多发性骨髓瘤 (MM) 癌细胞的经过验证的 NK CAR。针对表达 CS1 的 MM 细胞的优化 CAR 该方法建立在我们团队的丰富经验之上。在强有力的初步数据的指导下，对细胞信号传导进行建模和表征以及研究 NK 细胞生物学，我们建议追求三个具体目标：（1）表征 CAR-的细胞内和细胞水平反应表达 NK 细胞；（2）开发计算模型来预测表达 CAR 的动态反应 NK 细胞；(3) 鉴定有效激活 NK 细胞的新型 CAR 结构。总的来说，我们提出的研究将产生对 CAR 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优化 NK-CAR 结构以用于癌症免疫治疗。通过深入了解细胞内 NK 细胞如何发挥作用，该研究将广泛影响癌症免疫治疗领域最终，这项研究将扩展我们对 NK 细胞激活的认识。 NK 细胞信号传导以及基于 NK-CAR 的其他肿瘤类型和癌症免疫疗法的设计标准我们的工作有可能释放 NK-CAR 细胞对癌症免疫的变革力量 - 治疗。