肿瘤细胞治疗研究
英文原题：CD70-specific CAR NK cells expressing IL-15 for the treatment of CD19-negative B-cell malignancy.
我们的研究表明，在 B 细胞淋巴瘤治疗中，基于重复给药的 CAR NK 细胞疗法相比单次剂量的 CAR NK 细胞具有临床优势。
嵌合抗原受体（CAR）自然杀伤（NK）细胞不仅可借助CAR分子识别表达抗原的癌细胞清除肿瘤，也可通过NK细胞自身受体发挥作用。这克服了CAR-T细胞疗法的部分局限，为开发更安全、有效的现货型细胞疗法铺平道路。本研究构建了靶向CD70（淋巴瘤广谱靶点）的第四代CAR，含4-1BB共刺激结构域和白细胞介素15（IL-15）；随后使用Baboon包膜假型慢病毒载体，将其转导至脐带血来源NK细胞。与未转导NK细胞和靶向CD19的CAR-NK细胞相比，CD70-CAR NK细胞在体外和体内对CD19阴性B细胞淋巴瘤均表现出更强细胞毒活性。值得注意的是，接受两剂CD70-CAR NK细胞的小鼠肿瘤得到有效清除，同时血浆IL-15浓度升高，CAR-NK细胞增殖增强且持久性提高。本研究提示，与单次给药相比，重复给药的CAR-NK细胞疗法在治疗B细胞淋巴瘤方面具有临床优势。
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.
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