文章：

靶向HER2阳性实体瘤的CAR NK细胞疗法：CD44表达是调控HER2特异性CAR NK细胞疗效的关键因子

Targeting HER2-Positive Solid Tumors with CAR NK Cells: CD44 Expression Is a Critical Modulator of HER2-Specific CAR NK Cell Efficacy

原文发布日期：21 February 2025

DOI: 10.3390/cancers17050731

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:Monoclonal antibody therapies for HER2-positive tumors frequently encounter resistance, requiring alternative treatment strategies. This study investigates the use of natural killer (NK) cells expressing HER2-specific chimeric antigen receptor (CAR) to address this issue. CAR NK cells have several benefits over CAR T cells: they are less likely to cause severe side effects such as cytokine release syndrome and neurotoxicity, can be sourced from various origins, and do not trigger Graft versus Host Disease, making them ideal for “off-the-shelf” applications.Methods:We have generated NK-92 cell lines expressing first, second and third-generation HER2-specific CARs with CD28 and/or 41BB costimulatory domains using a retroviral transduction system, followed by FACS sorting and expansion to obtain pure HER2-CAR NK-92 cell products for functional benchmarking.Results:In vitro tests showed that these CAR NK cells were effective against both trastuzumab-sensitive (CD44−) and -resistant (CD44+) tumors in monolayer cultures. However, in three-dimensional spheroid models and in vivo xenografts, they were less effective against CD44+ trastuzumab-resistant tumors.Conclusions:This reduced efficacy highlights the significant role of the tumor microenvironment, particularly the extracellular matrix, in hindering the therapeutic potential of CAR NK cells. Despite the promising in vitro performance of CAR NK cells, this study emphasizes the need for improved strategies to enhance their penetration and effectiveness in resistant tumors: optimizing CAR constructs and devising methods to overcome extracellular matrix barriers are crucial for advancing CAR NK cell therapies in oncology.

摘要翻译： 

背景/目的：针对HER2阳性肿瘤的单克隆抗体疗法常面临耐药性问题，亟需开发替代治疗策略。本研究探讨了表达HER2特异性嵌合抗原受体（CAR）的自然杀伤（NK）细胞在此领域的应用潜力。相较于CAR T细胞，CAR NK细胞具有多重优势：引发细胞因子释放综合征及神经毒性等严重副作用的风险较低、来源广泛，且不会诱发移植物抗宿主病，使其成为理想的"即用型"治疗选择。 方法：我们通过逆转录病毒转导系统构建了表达第一、二、三代HER2特异性CAR的NK-92细胞系，这些CAR结构包含CD28和/或41BB共刺激结构域。经流式分选与扩增培养后，获得高纯度HER2-CAR NK-92细胞产品用于功能评估。 结果：体外实验显示，这些CAR NK细胞在单层培养体系中能有效杀伤曲妥珠单抗敏感型（CD44−）与耐药型（CD44+）肿瘤细胞。但在三维球体模型及体内异种移植模型中，其对CD44+曲妥珠单抗耐药肿瘤的杀伤效果显著减弱。 结论：这种疗效差异凸显了肿瘤微环境（尤其是细胞外基质）对CAR NK细胞治疗潜能的制约作用。尽管CAR NK细胞在体外展现出良好疗效，本研究强调必须开发新策略以增强其在耐药肿瘤中的浸润能力与治疗效果：优化CAR结构设计、制定克服细胞外基质屏障的方法，对推动CAR NK细胞疗法在肿瘤治疗领域的发展至关重要。

原文链接：

Targeting HER2-Positive Solid Tumors with CAR NK Cells: CD44 Expression Is a Critical Modulator of HER2-Specific CAR NK Cell Efficacy