Highly Efficient Generation of Transgenically Augmented CAR NK Cells Overexpressing CXCR4
Highly Efficient Generation of Transgenically Augmented CAR NK Cells Overexpressing CXCR4
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DOI：
10.3389/fimmu.2020.02028
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发表时间：
2020-08-28
影响因子：
7.3
通讯作者：
Hartmann, Jessica
中科院分区：
文献类型：
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作者：
Jamali, Arezoo;Hadjati, Jamshid;Hartmann, Jessica
自然杀伤（NK）细胞是癌症过继细胞治疗中值得注意的淋巴细胞亚群。NK细胞启动针对感染和恶性肿瘤的天然免疫应答，具有天然的细胞毒性，其不依赖于外来抗原识别。基于这些实质性特征，基因修饰NK细胞是免疫治疗的主要目标之一，但目前难以实现。最近，我们报道了一种在基因修饰的T细胞中具有显著功能的全人CAR 19构建体（huCAR 19）。在这里，我们显示了使用慢病毒载体将huCAR 19有效且稳定地基因递送至原代人NK细胞，其转导效率与使用NK细胞系实现的转导效率相当。这些huCAR 19 NK细胞显示出针对靶细胞的特异性和有效的细胞毒性活性。为了改善NK细胞向骨髓的归巢，我们用人CXCR 4基因增强huCAR 19 NK细胞，从而产生转基因增强的CAR NK细胞（TRACK）。与常规CAR NK细胞相比，TRACK在响应重组SDF-1或骨髓基质细胞时表现出增强的迁移能力，同时保留针对靶细胞的功能和细胞溶解活性。基于这些有希望的发现，TRACK可能成为临床应用中免疫治疗策略的新候选者。
Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK cells initiate innate immune responses against infections and malignancies with natural cytotoxicity, which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying NK cells is among the prime goals in immunotherapy but is currently difficult to achieve. Recently, we reported a fully human CAR19 construct (huCAR19) with remarkable function in gene-modified T-cells. Here, we show efficient and stable gene delivery of huCAR19 to primary human NK cells using lentiviral vectors with transduction efficiencies comparable to those achieved with NK cell lines. These huCAR19 NK cells display specific and potent cytotoxic activity against target cells. To improve homing of NK cells to the bone marrow, we augmented huCAR19 NK cells with the human CXCR4 gene, resulting in transgenically augmented CAR NK cells (TRACKs). Compared to conventional CAR NK cells, TRACKs exhibit enhanced migration capacity in response to recombinant SDF-1 or bone marrow stromal cells while retaining functional and cytolytic activity against target cells. Based on these promising findings, TRACKs may become a novel candidate for immunotherapeutic strategies in clinical applications.