Division of Hematology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.
GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
J Hematol Oncol. 2021 May 1;14(1):73. doi: 10.1186/s13045-021-01083-5.
Due to their efficient recognition and lysis of malignant cells, natural killer (NK) cells are considered as specialized immune cells that can be genetically modified to obtain capable effector cells for adoptive cellular treatment of cancer patients. However, biological and technical hurdles related to gene delivery into NK cells have dramatically restrained progress. Recent technological advancements, including improved cell expansion techniques, chimeric antigen receptors (CAR), CRISPR/Cas9 gene editing and enhanced viral transduction and electroporation, have endowed comprehensive generation and characterization of genetically modified NK cells. These promising developments assist scientists and physicians to design better applications of NK cells in clinical therapy. Notably, redirecting NK cells using CARs holds important promise for cancer immunotherapy. Various preclinical and a limited number of clinical studies using CAR-NK cells show promising results: efficient elimination of target cells without side effects, such as cytokine release syndrome and neurotoxicity which are seen in CAR-T therapies. In this review, we focus on the details of CAR-NK technology, including the design of efficient and safe CAR constructs and associated NK cell engineering techniques: the vehicles to deliver the CAR-containing transgene, detection methods for CARs, as well as NK cell sources and NK cell expansion. We summarize the current CAR-NK cell literature and include valuable lessons learned from the CAR-T cell field. This review also provides an outlook on how these approaches may transform current clinical products and protocols for cancer treatment.
由于其能够高效识别和裂解恶性细胞，自然杀伤 (NK) 细胞被认为是一种特殊的免疫细胞，可以通过基因修饰获得具有能力的效应细胞，用于癌症患者的过继细胞治疗。然而，与将基因递送入 NK 细胞相关的生物学和技术障碍极大地限制了该领域的进展。最近的技术进步，包括改进的细胞扩增技术、嵌合抗原受体 (CAR)、CRISPR/Cas9 基因编辑以及增强的病毒转导和电穿孔，为全面生成和表征基因修饰的 NK 细胞提供了可能。这些有前途的发展使科学家和医生能够设计出更好的 NK 细胞在临床治疗中的应用。值得注意的是，通过 CAR 重定向 NK 细胞为癌症免疫治疗带来了重要的希望。使用 CAR-NK 细胞的各种临床前和有限数量的临床研究显示出了有希望的结果：在没有副作用的情况下有效消除靶细胞，例如在 CAR-T 疗法中观察到的细胞因子释放综合征和神经毒性。在这篇综述中，我们重点介绍了 CAR-NK 技术的细节，包括高效和安全的 CAR 构建体的设计以及相关的 NK 细胞工程技术：携带 CAR 的转基因的载体、CAR 的检测方法，以及 NK 细胞的来源和 NK 细胞的扩增。我们总结了目前的 CAR-NK 细胞文献，并从 CAR-T 细胞领域中吸取了宝贵的经验教训。这篇综述还展望了这些方法如何改变当前癌症治疗的临床产品和方案。
