Bastin Donald J, Kilgour Marisa K, Shorr Risa, Sabri Elham, Delluc Aurélien, Ardolino Michele, McComb Scott, Lee Seung-Hwan, Allan David, Ramsay Tim, Visram Alissa
Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Cancer Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Cytotherapy. 2025 Mar;27(3):350-364. doi: 10.1016/j.jcyt.2024.11.004. Epub 2024 Nov 23.
Chimeric antigen receptor (CAR) engineered NK cells (CAR-NK) are a novel approach to the immunotherapy of hematologic malignancies which seeks to overcome some of the challenges faced by CAR-T cells (CAR-T). With few published clinical studies, preclinical studies can identify strategies to accelerate clinical translation. We conducted a systematic review on the preclinical in vivo use of CAR-NK for the treatment of hematologic malignancies to assess these therapies in a holistic and unbiased manner.
Our protocol was registered with PROSPERO (ID: CRD42023438375). We performed a search of OVID MEDLINE, OVID Embase, and Embase for animal studies employing human CAR-NK cells in the treatment of hematologic malignancies. Screening of studies for eligibility criteria was performed in duplicate. Our primary outcomes were survival and reduction in tumor volume. Data extraction from individual experiments was performed by one reviewer using Digitizeit software and verified by a second reviewer. Meta-analysis and subgroup analyses were performed using Comprehensive Meta-Analysis software. Information for descriptive outcomes was extracted in duplicate by two independent reviewers. Risk of bias was assessed using the SYRCLE Risk of Bias Tool for Animal Studies.
A total of 34 papers met eligibility criteria. Overall, CD19 was the most common antigen targeted however there was substantial diversity in antigenic targets, source material for generating CAR-NK cells, and NK cell modifications. Mice treated with CAR-NK therapy survived significantly longer than untreated mice (median survival ratio of 1.18, 95% CI: 1.10-1.27, P < 0.001), and mice treated with nonengineered NK cells (median survival ratio 1.13, 95% CI: 1.03-1.23, P < 0.001). Similarly, treatment with CAR-NK significantly reduced the tumor burden when compared to untreated mice (ratio of mean tumor volume 0.23, 95% CI: 0.17-0.32, P < 0.001) or mice treated with nonengineered NK cells (ratio of mean tumor volume 0.37, 95% CI: 0.28-0.51, P < 0.001). Subgroup analysis showed that cotreatment with IL-15 reduced tumor volume but did not increase survival. In general, CAR-NK cell persistence was short but was increased by IL-15.
CAR-NK shows promise for the treatment of hematologic malignancies in preclinical models.
嵌合抗原受体（CAR）工程化自然杀伤细胞（CAR-NK）是血液系统恶性肿瘤免疫治疗的一种新方法，旨在克服CAR-T细胞（CAR-T）面临的一些挑战。由于已发表的临床研究较少，临床前研究可以确定加速临床转化的策略。我们对CAR-NK在临床前体内治疗血液系统恶性肿瘤的应用进行了系统评价，以全面、无偏倚的方式评估这些疗法。
我们的方案已在PROSPERO注册（ID：CRD42023438375）。我们在OVID MEDLINE、OVID Embase和Embase中检索了用人CAR-NK细胞治疗血液系统恶性肿瘤的动物研究。对研究的纳入标准进行了重复筛选。我们的主要结局是生存率和肿瘤体积的缩小。由一名审阅者使用Digitizeit软件从各个实验中提取数据，并由另一名审阅者进行验证。使用Comprehensive Meta-Analysis软件进行荟萃分析和亚组分析。描述性结局的信息由两名独立审阅者重复提取。使用动物研究的SYRCLE偏倚风险工具评估偏倚风险。
共有34篇论文符合纳入标准。总体而言，CD19是最常见的靶向抗原，但抗原靶点、产生CAR-NK细胞的原材料以及NK细胞修饰存在很大差异。接受CAR-NK治疗的小鼠存活时间明显长于未治疗的小鼠（中位生存比为1.18，95%CI：1.10-1.27，P<0.001），也长于接受非工程化NK细胞治疗的小鼠（中位生存比为1.13，95%CI：1.03-1.23，P<0.001）。同样，与未治疗的小鼠相比（平均肿瘤体积比为0.23，95%CI：0.17-0.32，P<0.001）或接受非工程化NK细胞治疗的小鼠相比（平均肿瘤体积比为0.37，95%CI：0.28-0.51，P<0.001），CAR-NK治疗显著降低了肿瘤负担。亚组分析表明，与IL-15联合治疗可缩小肿瘤体积，但不会提高生存率。一般来说，CAR-NK细胞的持久性较短，但IL-15可增加其持久性。
在临床前模型中，CAR-NK在治疗血液系统恶性肿瘤方面显示出前景。
