Metabolic reprogramming to improve EGFRvIII CAR T cell persistence

代谢重编程提高 EGFRvIII CAR T 细胞的持久性

基本信息

批准号：
10753084
负责人：
Nancie MacIver
金额：
$ 21.78万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10753084
关键词：
Metabolic reprogramming improve EGFRvIII CAR

项目摘要

ABSTRACT Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been successful against some liquid tumors, but has failed to cure solid tumors. A key reason for CAR T cell failure against solid tumors is antigen heterogeneity. However, pre-clinical studies of CAR T cells against solid tumors in animal models show some promise; in a brain tumor mouse model of glioblastoma, CAR T cells recognizing the EGFRvIII tumor-specific antigen are successful in eliminating tumor, but only against homogeneous tumor and only when mice first receive lymphodepletive host conditioning (via total body irradiation) prior to CAR T cell infusion. Although lymphodepletive host conditioning provides immunological space for CAR T cell expansion, it is problematic in the context of heterogeneous solid tumors, as it impairs endogenous host immunity which is critical for targeting alternative antigens found within the solid tumor. For that reason, successful CAR T cell treatment against solid heterogeneous tumors will require innovative methods to improve CAR T cell persistence to eliminate the need for host lymphodepletive conditioning, and allow for preservation of host endogenous immunity. To achieve this, we propose to utilize metabolic reprogramming of EGFRvIII CAR T cells. Many studies over the last decade have now clearly demonstrated a link between T cell differentiation, function, and metabolism. A predominantly oxidative metabolism supports T cell surveillance, survival, and memory, whereas a predominantly glycolytic metabolism supports biosynthesis to promote effector T cell proliferation and function, but is associated with decreased longevity. The objectives of this R21 proposal are to (1) utilize metabolic reprogramming of EGFRvIII CAR T cells to improve CAR T cell persistence in vitro and in vivo, and (2) test the ability of modified EGFRvIII CAR T cells delivered in the absence of lymphodepletive host conditioning to preserve the endogenous immune system and improve heterogeneous tumor killing. We hypothesize that methods that increase oxidative metabolism will improve CAR T cell persistence, eliminating the need for lymphodepletive host conditioning, maintaining host endogenous immunity, and ultimately improving heterogeneous tumor killing. To test our hypothesis, we will perform the following specific aims: 1) Identify genetic and pharmacological strategies to modify EGFRvIII CAR T cells for enhanced metabolic fitness to support persistence; and 2) Test if metabolically fit murine EGFRvIII CAR T cells delivered in the absence of lymphodepletive host conditioning preserve endogenous immunity. If successful, these approaches can be partnered in future studies with strategies to enhance endogenous host immunity against heterogeneous tumors and overcome a hostile immunosuppressive tumor environment. This work, while performed in a brain tumor model, would be relevant for CAR T cell therapy against multiple solid tumors.

抽象的使用嵌合抗原受体 (CAR) T 细胞的过继免疫疗法已成功对抗某些液体肿瘤，但未能治愈实体瘤。 CAR T细胞对抗实体瘤失败的一个关键原因是抗原异质性。然而，CAR T 细胞在动物模型中对抗实体瘤的临床前研究表明，承诺;在胶质母细胞瘤的脑肿瘤小鼠模型中，CAR T 细胞识别 EGFRvIII 肿瘤特异性抗原成功消除肿瘤，但仅针对同质肿瘤，并且仅当小鼠首先在 CAR T 细胞输注之前接受淋巴细胞清除宿主调节（通过全身照射）。虽然淋巴细胞清除宿主调节为 CAR T 细胞扩增提供了免疫空间，但在异质实体瘤的背景，因为它损害内源性宿主免疫，这对于靶向至关重要实体瘤内发现的替代抗原。因此，针对实体瘤的 CAR T 细胞治疗取得了成功异质性肿瘤需要创新方法来提高 CAR T 细胞的持久性，以消除这种需要用于宿主淋巴细胞清除调节，并允许保留宿主内源性免疫。为了实现这一目标，我们建议利用 EGFRvIII CAR T 细胞的代谢重编程。过去十年的许多研究现在已经清楚地证明了 T 细胞分化、功能和代谢之间的联系。主要是一个氧化代谢支持 T 细胞监视、生存和记忆，而主要是糖酵解代谢代谢支持生物合成以促进效应 T 细胞增殖和功能，但与寿命缩短。该 R21 提案的目标是 (1) 利用 EGFRvIII 的代谢重编程 CAR T细胞提高CAR T细胞在体外和体内的持久性，以及（2）测试修饰的EGFRvIII的能力 CAR T 细胞在没有淋巴细胞清除宿主条件的情况下递送，以保持内源性免疫系统并提高异质肿瘤杀伤能力。我们假设增加氧化的方法新陈代谢将提高 CAR T 细胞的持久性，消除淋巴细胞清除宿主调理的需要，维持宿主内源性免疫，最终提高异质肿瘤杀伤能力。来测试我们的假设，我们将实现以下具体目标：1）确定遗传和药理学策略修改 EGFRvIII CAR T 细胞以增强代谢适应性以支持持久性； 2) 测试是否代谢适合在没有淋巴细胞清除宿主调理保存的情况下输送的小鼠 EGFRvIII CAR T 细胞内源性免疫。如果成功的话，这些方法可以在未来的研究中与策略结合起来增强宿主对异质性肿瘤的内源性免疫力并克服敌对的免疫抑制肿瘤环境。这项工作在脑肿瘤模型中进行，将与 CAR T 细胞疗法相关对抗多种实体瘤。