Induction of autophagy to enhance CAR-T cells in HIV cure approaches

诱导自噬增强 CAR-T 细胞在 HIV 治疗方法中的作用

• 批准号: 10653235
• 负责人: Matthew David Marsden
• 金额: $ 77.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-25 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653235
• 关键词: Affect; Antigen Presentation Pathway; Autophagocytosis; CAR T cell therapy; CD8-Positive T-Lymphocytes; Cell Therapy; Cell physiology; Cells; Cellular biology; Cellular immunotherapy; Chronic; Cytotoxic T-Lymphocytes; Data; Development; Disease remission; Drug Side Effects; Effectiveness; Engineering; Engraftment; Genetic Transcription; Goals; HIV; HIV Infections; HIV-1; Hematopoietic stem cells; Homeostasis; Immune; Immune System Diseases; Immunity; Immunologic Surveillance; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Interferons; Lymphocyte; Maintenance; Malignant Neoplasms; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Organelles; Peripheral; Play; Production; Recrudescences; Regulation; Reporting; Research; Role; Safety; Signal Pathway; Signal Transduction; Sirolimus; Spermidine; T cell differentiation; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Viral; Viral Load result; Withdrawal; adaptive immunity; antiretroviral therapy; bryostatin; chimeric antigen receptor; chimeric antigen receptor T cells; exhaust; exhaustion; functional restoration; humanized mouse; immune activation; improved; in vitro activity; in vivo; inhibitor; insight; metabolic fitness; mouse model; nonhuman primate; novel strategies; prevent; reactivation from latency; response; success; trafficking; transcriptome sequencing; treatment effect; viral rebound

ABSTRACT Chimeric Antigen Receptor (CAR) T-cells have emerged as a promising immunotherapy in controlling HIV-1 infection. However, CAR-T cells are also subject to immune dysfunction/exhaustion mediated by persistent inflammation during chronic HIV infection. Strategies to prevent exhaustion/restore functions of anti- HIV CAR-T cell are critical for ultimately achieving HIV functional cure. Our preliminary studies have showed that autophagy induction can improve mitochondria function and promote CAR-T cell cytotoxic T lymphocyte activity in vitro. Importantly, we found that induction of autophagy can prevent excessive IFN-I signaling and in vivo treatment with autophagy inducer rapamycin in chronically HIV infected humanized mice can decrease inflammation, restore exhausted anti-viral T cell function, and reduce viral loads. In addition, we found that autophagy inducers such as rapamycin allow efficient HIV-1 latency reversal by PKC activator bryostatin-1 while reducing T cell activation associated immune toxicity. Therefore, we hypothesize that autophagy induction can enhance ‘kick and kill’ HIV cure approaches by improving the survival, persistence and function of anti-HIV CAR-T cells and facilitating effective and safe latency reversal by PKC modulators. We will utilize our well-established humanized mouse model engineered with anti-HIV CD4CAR T cells to investigate the therapeutic potentials of autophagy induction for HIV ‘kick and kill’ cure approaches. Our study will also provide mechanistic insights into the development of immune exhaustion and autophagy’s regulation of CAR-T cell function and will thus have a wide impact beyond HIV cure research.

抽象的 嵌合抗原受体 (CAR) T 细胞已成为一种有前途的免疫疗法，可控制 HIV-1 感染。然而，CAR-T 细胞也会受到以下因素介导的免疫功能障碍/衰竭的影响： 慢性艾滋病毒感染期间的持续炎症。防止耗尽/恢复抗病毒功能的策略 HIV CAR-T细胞对于最终实现HIV功能性治愈至关重要。我们的初步研究表明 认为自噬诱导可以改善线粒体功能并促进CAR-T细胞细胞毒性T淋巴细胞 体外活性。重要的是，我们发现诱导自噬可以防止过度的 IFN-I 信号传导，并在 在慢性 HIV 感染的人源化小鼠中使用自噬诱导剂雷帕霉素进行体内治疗可以减少 炎症，恢复疲惫的抗病毒 T 细胞功能，并减少病毒载量。此外，我们发现 自噬诱导剂（如雷帕霉素）可通过 PKC 激活剂苔藓抑素-1 有效逆转 HIV-1 潜伏期 同时减少 T 细胞激活相关的免疫毒性。因此，我们推测自噬 诱导可以通过提高存活率、持久性和功能来增强“踢杀”艾滋病毒治疗方法 抗 HIV CAR-T 细胞，并通过 PKC 调节剂促进有效且安全的潜伏期逆转。我们将利用 我们完善的人源化小鼠模型采用抗 HIV CD4CAR T 细胞设计来研究 自噬诱导对于艾滋病毒“踢杀”治疗方法的治疗潜力。我们的研究还将提供 CAR-T细胞免疫耗竭发展机制和自噬调节 功能，因此将产生超出艾滋病毒治疗研究的广泛影响。