PDF(Pubmed)
Abstract：
UNASSIGNED: Chimeric antigen receptor (CAR) natural killer (NK) cells can eliminate tumors not only through the ability of the CAR molecule to recognize antigen-expressed cancer cells but also through NK-cell receptors themselves. This overcomes some of the limitations of CAR T cells, paving the way for CAR NK cells for safer and more effective off-the-shelf cellular therapy. In this study, CD70-specific (a pan-target of lymphoma) fourth-generation CAR with 4-1BB costimulatory domain and interleukin-15 (IL-15) was constructed and transduced into cord blood-derived NK cells by Baboon envelope pseudotyped lentiviral vector. CD70-CAR NK cells displayed superior cytotoxic activity in vitro and in vivo against CD19-negative B-cell lymphoma when compared with nontransduced NK cells and CD19-specific CAR NK cells. Importantly, mice that received 2 doses of CD70-CAR NK cells showed effective eradication of tumors, accompanied by increased concentration of plasma IL-15 and enhanced CAR NK cell proliferation and persistence. Our study suggests that repetitive administration-based CAR NK-cell therapy has clinical advantage compared with a single dose of CAR NK cells for the treatment of B-cell lymphoma.
摘要：
嵌合抗原受体（CAR）-NK细胞不仅可以通过CAR分子识别抗原表达的癌细胞的能力，还可以通过NK细胞受体本身来消除肿瘤。这克服了CAR-T细胞的一些局限性，为更安全、更有效的现成细胞治疗铺路CAR-NK细胞。在这项研究中,CD70，淋巴瘤的泛靶点，构建了具有4-1BB共刺激结构域和IL-15的特异性第四代CAR,并通过Baboon包膜假型Lenti载体将其转导至脐带血来源的NK细胞.当与未转导的NK细胞和CD19特异性CAR-NK细胞相比时,CD70-CARNK细胞在体外和体内对CD19阴性B细胞淋巴瘤表现出优异的细胞毒性活性。重要的是,小鼠接受两种剂量的CD70-CARNK细胞显示有效根除肿瘤，伴有血浆IL-15浓度增加和CAR-NK细胞增殖和持久性增强。我们的研究表明，与单剂量CAR-NK细胞治疗B细胞淋巴瘤相比，重复给药的CAR-NK细胞疗法具有临床优势。
