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

• 批准号: 10437931
• 负责人: Nancie MacIver
• 金额: --
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-07-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437931
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Anabolism; Animal Model; Antigens; Antitumor Response; Brain Neoplasms; CAR T cell therapy; Cell Respiration; Cell physiology; Clonal Expansion; Effector Cell; Environment; Failure; Future; Genetic; Glioblastoma; Glutamine; Goals; Heterogeneity; Human; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunologics; Impairment; In Vitro; Infusion procedures; Lead; Link; Liquid substance; Longevity; Memory; Memory impairment; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Mus; Patients; Pharmacology; Phase; Protocols documentation; Rest; Role; Solid; Solid Neoplasm; T cell differentiation; T memory cell; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Tumor Antigens; Whole-Body Irradiation; Work; chimeric antigen receptor; chimeric antigen receptor T cells; conditioning; cytokine; effector T cell; epidermal growth factor receptor VIII; improved; in vivo; innovation; metabolic fitness; metabolic profile; mouse model; novel strategies; oxidation; preclinical study; preservation; programs; tumor

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细胞的收养免疫疗法已经成功地针对某些液体 肿瘤，但无法治愈实体瘤。抗原抗原导致汽车T细胞衰竭的关键原因 异质性。然而，动物模型中对固体瘤的汽车T细胞的临床前研究表明 承诺;在胶质母细胞瘤的脑肿瘤小鼠模型中，识别EGFRVIII肿瘤特异性的CAR T细胞 抗原成功地消除了肿瘤，但仅针对均质肿瘤，并且仅在小鼠首次时才 在进输注之前，接收淋巴结蛋白宿主的调节（通过全身照射）。虽然 淋巴结治疗宿主条件为CAR T细胞扩展提供了免疫学空间，这是有问题的 异质实体瘤的背景，因为它会损害内源性宿主免疫，这对于靶向至关重要 在实体瘤中发现的替代抗原。因此，成功的汽车T细胞治疗针对固体 异质性肿瘤将需要创新的方法来改善CAR T细胞持久性以消除需求 用于宿主淋巴细胞论调节，并允许保存宿主内源性免疫。为此， 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 氧化代谢支持T细胞监测，存活和记忆，而主要的糖酵解 代谢支持生物合成以促进效应t细胞的增殖和功能，但与 寿命降低。该R21提案的目标是（1）使用EGFRVIII的代谢重编程 CAR T细胞在体外和体内改善CAR T细胞持久性，（2）测试改性EGFRVIII的能力 在没有淋巴结hod宿主条件的情况下，送达的CAR T细胞可保留内源性免疫 系统并改善异质性肿瘤杀死。我们假设增加氧化的方法 代谢将改善CAR T细胞的持久性，消除对淋巴结障碍宿主调节的需求， 保持宿主内源性免疫，并最终改善异质性肿瘤杀伤。测试我们的 假设，我们将执行以下特定目的：1）确定遗传和药理策略 修改EGFRVIII CAR T细胞，以增强代谢适应性以支持持久性； 2）测试如果代谢 在没有淋巴结hod宿主调节保存期的情况下，适合鼠EGFRVIII汽车T细胞 内源性免疫。如果成功的话，这些方法可以与以后的研究合作，以策略 增强内源性宿主免疫对异质肿瘤的免疫力，并克服敌对的免疫抑制 肿瘤环境。这项工作虽然在脑瘤模型中进行，但与CAR T细胞疗法有关 针对多个实体瘤。