Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer.,Clinical & Experimental Immunology

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Engineering of chimeric natural killer cell receptors to develop precision adoptive immunotherapies for cancer.
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-06-16 , DOI: 10.1111/cei.13478
J Obajdin ₁ , D M Davies ₁ , J Maher _{1,

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Affiliation

Natural killer (NK) cells are innate immune effectors which play a crucial role in recognizing and eliminating virally infected and cancerous cells. They effectively distinguish between healthy and distressed self through the integration of signals delivered by germline‐encoded activating and inhibitory cell surface receptors. The frequent up‐regulation of stress markers on genetically unstable cancer cells has prompted the development of novel immunotherapies that exploit such innate receptors. One prominent example entails the development of chimeric antigen receptors (CAR) that detect cell surface ligands bound by NK receptors, coupling this engagement to the delivery of tailored immune activating signals. Here, we review strategies to engineer CARs in which specificity is conferred by natural killer group 2D (NKG2D) or other NK receptor types. Multiple preclinical studies have demonstrated the remarkable ability of chimeric NK receptor‐targeted T cells and NK cells to effectively and specifically eliminate cancer cells and to reject established tumour burdens. Importantly, such systems act not only acutely but, in some cases, they also incite immunological memory. Moreover, CARs targeted with the NKG2D ligand binding domain have also been shown to disrupt the tumour microenvironment, through the targeting of suppressive T regulatory cells, myeloid‐derived suppressor cells and tumour vasculature. Collectively, these findings have led to the initiation of early‐phase clinical trials evaluating both autologous and allogeneic NKG2D‐targeted CAR T cells in the haematological and solid tumour settings.

中文翻译：

嵌合自然杀伤细胞受体的工程设计，以开发用于癌症的精确的过继免疫疗法。

天然杀伤（NK）细胞是先天性免疫效应物，在识别和消除病毒感染的癌细胞中起着至关重要的作用。通过整合种系编码的激活和抑制性细胞表面受体传递的信号，他们有效地区分了健康自我和痛苦自我。基因不稳定的癌细胞上压力标志物的频繁上调促使人们开发了利用这种先天受体的新型免疫疗法。一个重要的例子涉及嵌合抗原受体（CAR）的开发，该抗体检测被NK受体结合的细胞表面配体，并将这种结合与定制免疫激活信号的传递相结合。在这里，我们回顾了工程化CARs的策略，其中由自然杀手组2D（NKG2D）或其他NK受体类型赋予了特异性。多项临床前研究表明，靶向NK受体的嵌合T细胞和NK细胞具有显着的能力，能够有效，特异性地消除癌细胞并拒绝已建立的肿瘤负担。重要的是，这种系统不仅起急性作用，而且在某些情况下还引起免疫记忆。此外，以NKG2D配体结合结构域为靶点的CAR也被证明可以通过靶向抑制性T调节细胞，髓样抑制性细胞和肿瘤脉管系统来破坏肿瘤微环境。总而言之，这些发现导致了在血液学和实体瘤环境中评估自体和异体靶向NKG2D的CAR T细胞的早期临床试验的启动。

更新日期：2020-06-16

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