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: 10550477
• 负责人: Matthew David Marsden
• 金额: $ 79.6万
• 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/10550477
• 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; Life; 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; base; 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.

摘要 嵌合抗原受体（CAR）T细胞已经成为控制癌症的有希望的免疫疗法。 HIV-1感染。然而，CAR-T细胞也经历由免疫调节因子介导的免疫功能障碍/衰竭。 慢性HIV感染期间的持续炎症。预防抗-HCV衰竭/恢复抗-HCV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 自噬诱导可以改善线粒体功能，促进CAR-T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用自噬诱导剂雷帕霉素进行体内治疗可以降低 炎症，恢复耗尽的抗病毒T细胞功能，并降低病毒载量。此外，我们发现， 自噬诱导剂如雷帕霉素允许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，我们假设自噬 诱导可以通过提高存活率、持久性和功能来增强“踢死”HIV治疗方法。 抗HIV CAR-T细胞，并通过PKC调节剂促进有效和安全的潜伏期逆转。我们将利用 我们用抗HIV CD 4CAR T细胞工程化的完善的人源化小鼠模型来研究 自噬诱导对HIV“踢和杀”治疗方法的治疗潜力。我们的研究还将提供 CAR-T细胞免疫衰竭和自噬调控机制的研究进展 因此，它将产生超越艾滋病毒治疗研究的广泛影响。