Xie Y B, Zhang J Y, DU M L, Meng F P, Fu J L, Liu L M, Wang S S, Qu R, Lian F, Qiao F, Chen Y L, Gao Y Y, Xu R N, Shi M, Wang F S
Institute of Infectious Diseases, the Fifth Medical Center of PLA General Hospital, Beijing 100039, China.
Beijing Da Xue Xue Bao Yi Xue Ban. 2019 Jun 18;51(3):591-595. doi: 10.19723/j.issn.1671-167X.2019.03.032.
To evaluate the safety and efficacy of allogeneic natural killer (NK) cells in the treatment of primary hepatocellular carcinoma (HCC), and to elucidate the mechanism of NK cells therapy.
Twenty-one patients with primary HCC treated with allogeneic NK cells at the Fifth Medical Center of the PLA General Hospital were followed up for 1 year. Peripheral blood mononuclear cells (PBMCs) were isolated from patient-related donors and cultured in vitro for 15 days and infused to the patients in two consecutive days. Clinical data and laboratory data were collected and analyzed, including survival, clinical features, imaging changes, hematology, immunology, and biochemical indicators to evaluate the safety and efficacy of allogeneic NK cell therapy. The changes of peripheral blood lymphocyte subsets after treatment were also analyzed to explore the possible anti-tumor mechanisms.
(1) Of the 21 patients with primary HCC, 11 patients were treated once, 5 patients were treated twice, and 5 patients were treated 3 times. After allogeneic NK cells infusion, 10 patients had fever, 1 patient had slight hepatalgia and 1 patient had slight headache, no other adverse events occurred including acute and chronic graft-versus-host disease (GVHD). They resolved spontaneously within 8 hours without other treatment. (2) The total disease control rate was 76.2% during one-year follow-up. Among them, the patients with Barcelona clinic liver cancer (BCLC) stage A had a disease control rate of 100%, stable disease (SD) in 10 cases; BCLC stage B patients had a disease control rate of 60%, partial response (PR) in 1 case, and SD 2 in cases; BCLC stage C patients had a disease control rate of 50%, complete response (CR) in 1 case, and 2 cases of PR. (3) The frequencies of NK cells and CD8+ T cells in peripheral blood were significantly lower than that before at 24 hours after treatment, and the frequencies of CD4+ T cells and CD4/CD8 were significantly higher than the baseline.
Allogeneic NK cells have good safety and efficacy in the treatment of primary HCC. The anti-tumor effect of the allogeneic NK cells may play an important role in the activation of the patient's natural immune system and delay disease progression, suggesting that allogeneic NK cells combined with sorafenib may be a very effective treatment for advanced HCC, and further large-sample multicenter randomized controlled clinical trials are needed to validate this result.
评估异基因自然杀伤（NK）细胞治疗原发性肝细胞癌（HCC）的安全性和有效性，并阐明NK细胞治疗的机制。
对解放军总医院第五医学中心接受异基因NK细胞治疗的21例原发性HCC患者进行1年随访。从患者相关供体中分离外周血单个核细胞（PBMC），体外培养15天，连续两天输注给患者。收集并分析临床数据和实验室数据，包括生存情况、临床特征、影像学变化、血液学、免疫学和生化指标，以评估异基因NK细胞治疗的安全性和有效性。还分析了治疗后外周血淋巴细胞亚群的变化，以探讨可能的抗肿瘤机制。
（1）21例原发性HCC患者中，11例接受1次治疗，5例接受2次治疗，5例接受3次治疗。输注异基因NK细胞后，10例患者出现发热，1例患者出现轻微肝区疼痛，1例患者出现轻微头痛，未发生包括急性和慢性移植物抗宿主病（GVHD）在内的其他不良事件。它们在8小时内自行缓解，无需其他治疗。（2）1年随访期间总疾病控制率为76.2%。其中，巴塞罗那临床肝癌（BCLC）A期患者疾病控制率为100%，10例病情稳定（SD）；BCLC B期患者疾病控制率为60%，1例部分缓解（PR），2例SD；BCLC C期患者疾病控制率为50%，1例完全缓解（CR），2例PR。（3）治疗后24小时外周血中NK细胞和CD8+T细胞频率显著低于治疗前，CD4+T细胞频率和CD4/CD8显著高于基线。
异基因NK细胞治疗原发性HCC具有良好的安全性和有效性。异基因NK细胞的抗肿瘤作用可能在激活患者自然免疫系统和延缓疾病进展中起重要作用，提示异基因NK细胞联合索拉非尼可能是晚期HCC的一种非常有效的治疗方法，需要进一步的大样本多中心随机对照临床试验来验证这一结果。
