Enhancing HSPC CAR-mediated immunity in vivo

项目1：摘要/摘要 这项研究的目标是一种HIV-1治疗策略，该策略试图增加和优化抗HIV细胞免疫反应，这在控制体内HIV复制方面发挥着关键作用。由于HIV感染细胞库的持久性和持久性，联合抗逆转录病毒治疗（ART）不足以从体内根除HIV-1，患者必须在其余生中继续接受治疗。在没有ART治疗的情况下实现HIV-1治愈或缓解将需要增强和持续有效的抗病毒免疫应答。目前的大多数努力主要集中在通过外周T细胞的遗传修饰来增强免疫力，而我们的目标是通过用优化的抗HIV嵌合抗原受体（CAR）分子修饰自体造血干/祖细胞（HSPC）来产生终身抗HIV应答。此外，表达这种CAR分子的基因治疗载体还含有抗HIV基因，可以保护新开发的含有载体的T细胞免受感染。我们还将探索免疫和基因组合疗法，以提高基于CAR HSPC的疗法的安全性、性能和疗效。我们将使用一种具有替代系统的小鼠模型，该模型重现了人类免疫系统和HIV发病机制，以选择最佳CAR载体和最佳联合治疗设计，以最大限度地提高CAR细胞的体内功能。我们将在SHIV+感染、抗逆转录病毒药物治疗的非人灵长类动物（NHP）中评估我们的主要CAR候选物和联合治疗，以最好地模拟人类临床环境。我们提出的研究将提供关键的见解，并为许多基于HSPC的CAR免疫疗法的研究性新药（IND）开发铺平道路。

Project 1: Summary/Abstract The proposed research targets an HIV-1 cure strategy that attempts to increase and optimize anti-HIV cellular immune responses, which play a critical role in the control of HIV replication in the body. Due to the durability and persistence of reservoirs of HIV infected cells, combined antiretroviral treatment (ART) is insufficient in eradicating HIV-1 from the body and the patients have to remain on treatment for the rest of their lives. Achieving HIV-1 cure or remission without ART treatment will require the enhancement and persistence of effective antiviral immune responses. Most current efforts primarily focus on enhancing immunity via genetic modification of peripheral T cells while we aim at creating lifelong anti-HIV responses by modifying autologous Hematopoietic Stem/Progenitor Cells (HSPCs) with an optimized anti-HIV Chimeric Antigen Receptor (CAR) molecule. In addition, the gene therapy vector expressing this CAR molecule also contains anti-HIV genes, which protect the newly developed, vector-containing T cells from infection. We will also explore immune and gene combination therapies to improve the safety, performance, and efficacy of the CAR HSPC-based therapy. We will use a mouse model with a surrogate system that recapitulates the human immune system and HIV pathogenesis, to select for the best CAR vector and best combination therapy design to maximize the in vivo functionality of CAR cells. We will evaluate our lead CAR candidates and combination therapy in SHIV+ infected, anti-retroviral drug-treated non-human primates (NHPs) to best mimic the human clinical setting. Our proposed study will provide crucial insights and pave the way for investigational new drug (IND) development of numerous HSPC-based CAR immunotherapies.