肿瘤细胞治疗研究
英文原题：Lipid nanoparticle-mediated in vivo generation of panCAR immune cells for solid tumor immunotherapy.
利用嵌合抗原受体（CAR）对免疫细胞进行基因工程改造的过继性细胞疗法，由于免疫抑制性肿瘤微环境（TME）以及体外细胞操作在物流方面的挑战，在实体瘤中的疗效有限。
利用嵌合抗原受体（CAR）对免疫细胞进行基因工程的过继性细胞疗法，由于免疫抑制性肿瘤微环境（TME）以及离体细胞操作的后勤挑战，在实体瘤中显示出有限的效果。在此，我们介绍一种免疫细胞趋向性脂质纳米颗粒（LNP）平台，该平台能够实现CAR编码mRNA的全身递送，用于体内生成panCAR免疫细胞。单次静脉注射该LNP系统即可高效且短暂地工程化脾脏、骨髓和外周血中的T细胞、巨噬细胞、树突状细胞和NK细胞，产生协同的多谱系抗肿瘤反应。以人表皮生长因子受体2（HER2）作为CAR靶点，我们证明重复给予用HER2-CAR mRNA配制的LNP（LNP-panCAR HER2）在三种小鼠同系异种移植肿瘤模型中有效抑制肿瘤生长并延长总生存期，且未引起明显副作用。对治疗肿瘤的免疫分析揭示了TME重塑，向免疫刺激表型转变，其特征为M2样巨噬细胞减少和效应T细胞亚群存在增加。我们的发现确立了LNP-panCAR作为一个广泛适用的、即用型体内CAR细胞治疗平台，用于实体瘤免疫治疗及其他领域。
Adoptive cell therapies that genetically engineer immune cells with chimeric antigen receptors (CARs) have shown limited success against solid tumors due to the immunosuppressive tumor microenvironment (TME) and logistical challenges of ex vivo cell manipulation. Here, we introduce an immune cell-tropic lipid nanoparticle (LNP) platform that enables systemic delivery of CAR-encoding mRNA for the in vivo generation of panCAR immune cells. A single intravenous injection of this LNP system efficiently and transiently engineers T cells, macrophages, dendritic cells, and NK cells across the spleen, bone marrow, and peripheral blood, yielding a synergistic, multilineage antitumor response. Using human epidermal growth factor receptor 2 (HER2) as a CAR target, we demonstrate that repeated administration of LNP formulated with HER2-CAR mRNA (LNP-panCAR HER2 ) effectively inhibits tumor growth and prolongs overall survival in three murine syngeneic xenograft tumor models, without causing obvious side effects. Immune profiling of treated tumors reveals a remodeled TME with a shift toward an immunostimulatory phenotype, characterized by reduced M2-like macrophages and an increased presence of effector T cell subsets. Our findings establish LNP-panCAR as a broadly applicable, off-the-shelf in vivo CAR cell therapy platform for solid tumor immunotherapy and beyond.
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