Shimasaki Noriko, Coustan-Smith Elaine, Kamiya Takahiro, Campana Dario
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Cytotherapy. 2016 Nov;18(11):1422-1434. doi: 10.1016/j.jcyt.2016.06.013. Epub 2016 Aug 3.
The capacity of natural killer (NK) cells to recognize and kill transformed cells suggests that their infusion could be used to treat cancer. It is difficult to obtain large numbers of NK cells ex vivo by exposure to cytokines alone but the addition of stimulatory cells to the cultures can induce NK cell proliferation and long-term expansion. Some of these methods have been validated for clinical-grade application and support clinical trials testing feasibility and safety of NK cell administration. Early data indicate that ex vivo expansion of NK cells from healthy donors or from patients with cancer is robust, allowing multiple infusions from a single apheresis. NK cells can transiently expand in vivo after infusion. Allogeneic NK cells are not direct effectors of graft-versus-host disease but this may occur if donor NK cells are infused after allogeneic hematopoietic stem cell transplant, which may activate T cell alloreactivity. NK cells can be directed with antibodies, or engineered using either transient modification by electroporation of mRNA or prolonged gene expression by viral transduction. Thus, expanded NK cells can be armed with activating receptors that enhance their natural anti-tumor capacity or with chimeric antigen receptors that can redirect them towards specific tumor targets. They can also be induced to express cytokines that promote their autonomous growth, further supporting their in vivo expansion. With the implementation of these approaches, expanded and armed NK cells should ultimately become a powerful component of immunotherapy of cancer.
自然杀伤（NK）细胞识别并杀死转化细胞的能力表明，输注NK细胞可用于治疗癌症。仅通过暴露于细胞因子在体外很难获得大量NK细胞，但在培养物中添加刺激细胞可诱导NK细胞增殖和长期扩增。其中一些方法已通过临床级应用验证，并支持测试NK细胞给药可行性和安全性的临床试验。早期数据表明，从健康供体或癌症患者体外扩增NK细胞效果良好，单次采集的细胞可进行多次输注。NK细胞输注后可在体内短暂扩增。异体NK细胞不是移植物抗宿主病的直接效应细胞，但如果在异体造血干细胞移植后输注供体NK细胞，可能会激活T细胞同种异体反应性，从而引发移植物抗宿主病。NK细胞可用抗体进行定向，或通过mRNA电穿孔的瞬时修饰或病毒转导的长期基因表达进行工程改造。因此，扩增后的NK细胞可配备增强其天然抗肿瘤能力的激活受体，或配备可将其重定向至特定肿瘤靶点的嵌合抗原受体。它们还可被诱导表达促进自身生长的细胞因子，进一步支持其在体内的扩增。随着这些方法的实施，扩增并武装后的NK细胞最终应会成为癌症免疫治疗的有力组成部分。
