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：
10542442
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/10542442
关键词：
Address Adherence Alleles Allogenic Anti-Retroviral Agents Autoimmune Binding Bispecific Antibodies 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 Periodicals 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 Visit acute infection antiretroviral therapy cancer immunotherapy cancer therapy chimeric antigen receptor chimeric antigen receptor T cells chronic infection clinical application coping 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 prototype receptor binding reconstitution response self-renewal side effect stem stem cell delivery 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.

项目概要/摘要虽然嵌合抗原受体 (CAR) 基因疗法最初在大约 15 年前尝试用于治疗 HIV，但后来被放弃，但它最近显示出越来越多的使用和治疗癌症的前景。该项目重新审视了这种针对 HIV 的方法，解决了过去阻碍其成功对抗 HIV 的关键障碍，包括利用造血干前体细胞 (HSPC) 在体内生成功能性且持久的 CAR T 细胞，以及基于广泛中和作用生成新型 CAR抗体 (bNAb) 和 CAR 组合可防止病毒逃逸。我们的具体目标是： 1. 优化 bNAb CAR 转导的 HSPC 的植入。 CAR T 细胞将从 HSPC 开始完全在体内发育，避免了离体 T 细胞扩增和转导的注意事项，从而提供终生的自我更新来源。移植将在重现 T 细胞发育的人源化小鼠模型（CD34 小鼠，是用成人捐献者的血液干细胞重建的免疫缺陷小鼠）中进行测试和优化。 2. 生成双特异性组合 bNAb CAR，以减少 HIV-1 逃逸的选择。新型 CAR 将使用新的双特异性抗体技术进行设计，从而创建双特异性 CAR。 3.选择体内抗病毒广度最佳的CAR组合。双特异性 CAR 的双重组合将在 CD34- 小鼠模型中与人工多样化的 HIV-1 准种进行体内挑战，以确定有效遏制的组合，类似于联合抗逆转录病毒治疗。这些研究将为成功使用 CAR 基因疗法治疗 HIV 感染的新方法奠定基础，这将是未来治疗策略的重要组成部分。