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Therapeutic Anti-HIV Chimeric Antigen Receptors Via Stem Cell Delivery

通过干细胞递送治疗性抗 HIV 嵌合抗原受体

基本信息

批准号：
9922602
负责人：
SCOTT G KITCHEN
金额：
$ 76.83万
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：
2020
资助国家：
美国
起止时间：
2020-01-16 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922602
关键词：
Address Adherence Alleles Allogenic Anti-Retroviral Agents Antibodies Antiviral Agents Autoimmune Process Binding Bone Marrow Transplantation Bypass CD3 Antigens CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Caucasians Cell surface Cells Clinical Clinical Trials Containment Cytomegalovirus Infections Cytoplasmic Protein Cytotoxic T-Lymphocytes Data Disadvantaged Disease Progression Down-Regulation Engraftment Epitopes Exclusion Face Failure Future Genome Scan HIV HIV Envelope Protein gp120 HIV Infections HIV therapy HIV-1 Hematopoietic Hematopoietic stem cells Histocompatibility Antigens Class I Human Immune Immune system Immunodeficient Mouse Immunologics In Vitro Individual Infection Length Macaca Major Histocompatibility Complex Malignant Neoplasms Morbidity - disease rate Mus Pathway interactions Periodicity Persons Pharmaceutical Preparations Pharmacotherapy Play Proteins Race Role SIV Scanning Source Surface T-Cell Development T-Cell Receptor T-Cell Receptor Genes T-Lymphocyte Technology Testing Therapeutic Viral Viremia Virus Virus Diseases acute infection antiretroviral therapy base cancer immunotherapy cancer therapy chimeric antigen receptor chimeric antigen receptor T cells chronic infection clinical application cost cytotoxic CD8 T cells design gene therapy genetic evolution human adult stem cell humanized mouse in vivo interest mortality risk mouse model neutralizing antibody novel novel strategies precursor cell prevent receptor binding reconstitution response self-renewal side effect stem stem cells success transmission process viral resistance virus genetics

项目摘要

PROJECT SUMMARY / ABSTRACT While chimeric antigen receptor (CAR) gene therapy was initially tried and abandoned for HIV about 15 years ago, it has recently shown increasing usage and promise for treating cancer. This project revisits this approach for HIV, addressing the key barriers that prevented its success against HIV in the past, including harnessing hematopoietic stem precursor cells (HSPCs) to generate functional and durable CAR T cells in vivo, and generating novel CARs based on broadly neutralizing antibodies (bNAbs) and CAR combinations to prevent viral escape. Our specific aims are: 1. To optimize engraftment of bNAb CAR-transduced HSPCs. CAR T cells would develop entirely in vivo starting from HSPCs, avoiding the caveats of ex vivo T cell expansion and transduction to provide a lifelong self-renewing source. Engraftment will be tested and optimized in a humanized mouse model that recapitulates T cell development (CD34-mice, which are immunodeficient mice reconstituted with blood stem cells from adult human donors). 2. To generate bi-specific combined bNAb CARs to reduce options for HIV-1 escape. Novel CARs will be designed using new bi-specific antibody technologies, creating bi-specific CARs. 3. To select CAR combinations with the best antiviral breadth in vivo. Dual combinations of bi-specific CARs will be challenged in vivo in the CD34- mouse model with artificially diverse HIV-1 quasispecies to determine combinations with effective containment, analogous to combination antiretroviral therapy. These studies will lay the groundwork for successful new approaches to treating HIV infection with CAR gene therapy, which will be a valuable component in future cure strategies.

项目摘要/摘要虽然嵌合抗原受体(CAR)基因疗法最初是为了治疗HIV而尝试，但在大约15年前就被放弃了，但最近它在治疗癌症方面显示出越来越多的用途和前景。该项目回顾了这种针对艾滋病毒的方法，解决了过去阻止其成功对抗艾滋病毒的关键障碍，包括利用造血干细胞(HSPC)在体内产生功能强大和持久的CAR T细胞，以及基于广泛中和抗体(BNAbs)和CAR组合生成新的CAR以防止病毒逃逸。我们的具体目标是： 1.优化bNAb车载HSPC的植入。CAR T细胞将从HSPC开始完全在体内发育，避免了T细胞体外扩增和转导的限制，提供了一个终身自我更新的来源。植入将在重塑T细胞发育的人源化小鼠模型中进行测试和优化(CD34小鼠，这是由成年人类捐赠者的血液干细胞重组而成的免疫缺陷小鼠)。 2.生成双特异性组合bNAb汽车，以减少艾滋病毒-1逃脱的选择。新型汽车将使用新的双特异性抗体技术进行设计，创造出双特异性汽车。 3.筛选体内抗病毒广度最佳的CAR组合。双特异性CARS的双重组合将在CD34小鼠模型中与人工多样化的HIV-1准种一起在体内受到挑战，以确定具有有效遏制的组合，类似于组合抗逆转录病毒治疗。这些研究将为用CAR基因疗法治疗艾滋病毒感染的成功新方法奠定基础，这将是未来治疗策略中有价值的组成部分。