Department of Infectious Diseases, Nankai University Second People's Hospital, Tianjin 300192, China.
Department of Infectious Diseases, Public Health Clinical Center of Chengdu, Chengdu, Sichuan 610066, China.
Chin Med J (Engl). 2020 Dec 5;133(23):2803-2807. doi: 10.1097/CM9.0000000000001189.
Allogeneic natural killer (NK) cell immunotherapy is recognized as a promising anti-tumor strategy, but whether it plays a role in poor CD4 recovery among human immunodeficiency virus type 1 (HIV-1) infected patients is unknown. This study aimed to investigate the safety and effectiveness of allogeneic NK cells immunotherapy on HIV-1 immunological non-responders (INRs) receiving antiretroviral therapy (ART).
From February to April 2018, a prospective, randomized, controlled, open-label clinical trial, which enrolled 20 HIV-1 INRs following specific inclusion criteria, was conducted at Nankai University Second People's Hospital. Participants were randomly allocated (simple randomization 1:1) to either the combined treatment (NK + ART) group (n = 10) or the control (ART) group (n = 10). The allogenic highly activated NK cells from killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen (HLA)-Cw mismatched healthy donor were prepared (10 cells in each injection) and intravenously infused to each recruited patient of NK+ART group in three courses. Key immune parameters (CD4 count, CD8 count, CD4/CD8 ratio), laboratory tests (count of blood cells, biochemistry panel) and symptoms at baseline and at month 1, 3, 6, 9, 12, and 24 were measured/collected to analyze the safety and efficacy of the therapy. Comparisons were between the seven time-points of both groups using repeated measurement analysis of variance (ANOVA) test. Generalized estimating equations (GEE) model was performed to evaluate the overall effect of the NK+ART group vs. the ART group.
From baseline to 24 months, we noted a mean CD4 count augmentation (139 to 243 cells/μL) in the NK + ART group and (144 to 176 cells/μL) in the ART group (difference, 67; 95% CI, 10 to 124; P = 0.024). Our estimations revealed that NK+ART group could improve CD4 level (β = 54.59, P = 0.006) and CD8 level (β = 322.47, P = 0.010) on average among the six measurements compared with the ART group. Only two (2/10, 20%) participants in the NK+ART group developed a transient mild fever after the first course.
This preliminary study informs that HIV-1 INRs, allogenic NK cells immunotherapy is safe and could significantly improve CD4 recovery but not CD4/CD8 ratio. The practical effects, however, need long-term follow-up observations. Further study on the potential underlying mechanism is warranted. REGISTRATION INFO:: www.chictr.org.cn/showproj.aspx?proj=34912 (No. ChiCTR1900020634).
同种异体自然杀伤 (NK) 细胞免疫疗法被认为是一种有前途的抗肿瘤策略，但它在人类免疫缺陷病毒 1 (HIV-1) 感染患者中是否对 CD4 恢复不良起作用尚不清楚。本研究旨在探讨同种异体 NK 细胞免疫疗法对接受抗逆转录病毒治疗 (ART) 的 HIV-1 免疫无应答者 (INRs) 的安全性和有效性。
2018 年 2 月至 4 月，在南开大学第二人民医院进行了一项前瞻性、随机、对照、开放标签的临床试验，共纳入了 20 名符合特定纳入标准的 HIV-1 INRs。参与者被随机分配（简单随机化 1:1）至联合治疗（NK+ART）组（n=10）或对照组（ART）组（n=10）。从 KIR/HLA-Cw 错配的健康供体中制备同种异体高活性 NK 细胞（每次注射 10 个细胞），并分三批静脉输注至 NK+ART 组的每位入组患者。在基线和第 1、3、6、9、12 和 24 个月测量/收集关键免疫参数（CD4 计数、CD8 计数、CD4/CD8 比值）、实验室检查（血细胞计数、生化指标）和症状，以分析治疗的安全性和疗效。使用重复测量方差分析 (ANOVA) 检验比较两组的七个时间点。使用广义估计方程 (GEE) 模型评估 NK+ART 组与 ART 组的总体效果。
从基线到 24 个月，我们观察到 NK+ART 组的 CD4 计数增加（139 至 243 个/μL），ART 组的 CD4 计数增加（144 至 176 个/μL）（差异，67；95%CI，10 至 124；P=0.024）。我们的估计表明，与 ART 组相比，NK+ART 组在六次测量中的平均 CD4 水平（β=54.59，P=0.006）和 CD8 水平（β=322.47，P=0.010）有所提高。NK+ART 组仅 2 名（2/10，20%）参与者在第一疗程后出现短暂的轻度发热。
这项初步研究表明，HIV-1 INRs 接受同种异体 NK 细胞免疫治疗是安全的，可显著改善 CD4 恢复，但不能改善 CD4/CD8 比值。然而，实际效果需要长期随访观察。需要进一步研究其潜在的机制。
www.chictr.org.cn/showproj.aspx?proj=34912（注册号：ChiCTR1900020634）。
