文章：

体内CAR-T细胞生成用于治疗癌症和自身免疫性疾病

In vivo CAR T cell generation to treat cancer and autoimmune disease

原文发布日期：2025-06-19

DOI: 10.1126/science.ads8473

类型: Research Article

开放获取: 否

文章简介：

Editor’s summary

Chimeric antigen receptor (CAR)–T cell therapies have been highly successful for treating B cell malignancies and also have potential for the treatment of autoimmune disease. However, complex manufacturing and conditioning regimens have limited their accessibility and scalability. Hunter et al. report a gene-delivery system to generate CAR-T cells in vivo by dosing of a CD8-targeted lipid nanoparticle carrying anti-CD19 CAR mRNA (see the Perspective by Peche and Gottschalk). Data from rodent and nonhuman primate (NHP) models demonstrated tumor control. In autoimmune models, deep and transient depletion of B cells was observed in the blood and tissues of NHPs, resulting in an “immune reset.” Such a strategy may provide an off-the-shelf, nonviral, and scalable alternative to ex vivo CAR-T cell immunotherapy. —Priscilla N. Kelly

Abstract

Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.

简介翻译： 

编者摘要

嵌合抗原受体（CAR）T细胞疗法在治疗B细胞恶性肿瘤方面非常成功，并且有潜力用于治疗自身免疫性疾病。然而，复杂的制造和调节方案限制了其可及性和可扩展性。Hunter等人报告了一种基因递送系统，通过剂量投送携带抗CD19 CAR mRNA的CD8靶向脂质纳米颗粒，在体内生成CAR-T细胞（参见Peche和Gottschalk的视角）。来自啮齿动物和非人灵长类动物（NHP）模型的数据显示了肿瘤控制。在自身免疫模型中，在NHP的血液和组织中观察到B细胞的深度和短暂耗竭，导致了“免疫重置”。这种策略可能为体外CAR-T细胞免疫疗法提供一种现成的、非病毒的、可扩展的替代方案。—Priscilla N. Kelly

摘要

嵌合抗原受体（CAR）T细胞疗法改变了B细胞恶性肿瘤的治疗。然而，其更广泛的应用受到复杂制造过程和淋巴清除化疗的必要性的限制，限制了患者的可及性。我们提出了一种体内工程策略，使用靶向脂质纳米颗粒（tLNPs）将信使RNA递送至特定的T细胞亚群。这些tLNPs在健康供体和自身免疫患者样本中重编程了CD8+ T细胞，体内剂量投送导致人源化小鼠中的肿瘤控制和食蟹猴中的B细胞耗竭。在食蟹猴中，耗竭后重建的B细胞主要是初始B细胞，表明免疫系统重置。通过消除复杂体外制造的要求，这个tLNP平台有潜力使CAR T细胞疗法更加可及，并适用于更多的临床适应症。

原文链接：

In vivo CAR T cell generation to treat cancer and autoimmune disease