Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate (NHP) model of HIV infection, we evaluated two CAR-based gene therapy approaches. In the ACT approach, we used cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR T cells. We observed limited persistence and expansion of anti-HIV CAR T cells, which led to minimal control of the virus. In our stem cell-based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells . We observed CAR-expressing T cell expansion, which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest that a stem cell-based CAR T cell approach may be superior in generating long-term persistence and functional antiviral responses against HIV infection.

中文翻译：

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与离体转导的 CAR T 细胞相比，干细胞衍生的 CAR T 细胞表现出更强的持久性、运输能力和病毒控制能力

使用表达嵌合抗原受体 (CAR) 的 T 细胞的过继细胞疗法 (ACT) 是治疗恶性肿瘤和慢性病毒感染的热门研究领域。基于 ACT 的 CAR 疗法的局限性之一是缺乏最佳细胞功能的持久性和维持。因此，需要增强表达 CAR 的 T 细胞的功能和维持的替代策略。在我们使用人源化骨髓/肝脏/胸腺 (BLT) 小鼠模型和非人灵长类 (NHP) HIV 感染模型的研究中，我们评估了两种基于 CAR 的基因治疗方法。在 ACT 方法中，我们使用细胞因子增强和预处理来产生更持久的抗 HIV CAR T 细胞。我们观察到抗 HIV CAR T 细胞的持久性和扩增有限，这导致对病毒的控制有限。在我们基于干细胞的方法中，我们用抗 HIV CAR 修饰造血干/祖细胞 (HSPC)，以产生抗 HIV CAR T 细胞。我们观察到表达 CAR 的 T 细胞扩增，从而更好地抑制血浆病毒载量。受感染的 NHP 中的 HSPC 衍生的 CAR 细胞在多个组织中表现出优异的运输和持久性。我们的研究结果表明，基于干细胞的 CAR T 细胞方法在针对 HIV 感染产生长期持久性和功能性抗病毒反应方面可能更胜一筹。