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

基本信息

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
项目类别：
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

项目摘要

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细胞已成为有望控制的免疫疗法 HIV-1感染。但是，CAR-T细胞也受到免疫功能障碍/疲惫的影响慢性艾滋病毒感染期间持续注射。防止抗疲劳/恢复抗功能的策略 HIV CAR-T细胞对于最终实现HIV功能治疗至关重要。我们的初步研究表明自噬诱导可以改善线粒体功能并促进CAR-T细胞毒性T淋巴细胞体外活性。重要的是，我们发现自噬的诱导可以防止过量的IFN-I信号传导和在长期感染的人源性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，并减少病毒载荷。此外，我们发现诸如雷帕霉素之类的自噬诱导剂可以通过PKC激活剂Bryostatin-1允许有效的HIV-1潜伏期逆转同时还原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改善生存，持久性和功能来增强“踢和杀死”的艾滋病毒治疗方法 PKC调节剂的抗HIV CAR-T细胞和支持有效且安全的潜伏期逆转。我们将利用我们建立的人性化小鼠模型由抗HIV CD4CAR T细胞设计，以研究自噬诱导艾滋病毒“踢和杀死”方法的治疗潜力。我们的研究也将提供对免疫耗尽和自噬对CAR-T细胞的调节的发展的机械洞察力功能，因此将在HIV治疗研究之外产生广泛的影响。