供者淋巴细胞输注治疗无效的移植后复发患者过继性回输NK细胞的免疫学变化和临床疗效  

Immunological changes and clinical efficacy of donor derived adoptive NK cells infusion in relapsed acute leukaemia patients with no response to donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation

作　　者：曹勋红 王志东[1] 韩伟[1] 陈育红[1] 唐菲菲[1] 孙于谦[1] 王景枝[1] 许兰平[1] 张晓辉[1] 王昱[1] 刘开彦[1] 黄晓军[1] 赵翔宇(指导)[1] CAO Xunhong;WANG Zhidong;HAN Wei;CHEN Yuhong;TANG Feifei;SUN Yuqian;WANG Jingzhi;XU Lanping;ZHANG Xiaohui;WANG Yu;LIU Kaiyan;HUANG Xiaojun;ZHAO Xiangyu(Peking University People's Hospital,Peking University Institute of Hematology,National Clinical Research Center for Hematological Diseases,Beijing 100044,China)

机构地区：[1]北京大学人民医院,北京大学血液研究所,国家血液系统疾病临床医学研究中心,北京100044

出　　处：《中国免疫学杂志》2022年第16期1993-2000,共8页Chinese Journal of Immunology

基　　金：国家自然科学基金(81670166,81870140,82070184);北京大学人民医院研究与发展基金(RDX2019-14)资助。

摘　　要：目的:探讨异基因造血干细胞移植后(allo-HSCT)复发患者在供者淋巴细胞回输(DLI)治疗无效后过继性回输NK细胞后的免疫学变化及临床疗效。方法:选取2011年2月至2014年1月于北京大学血液病研究所进行allo-HSCT且移植后复发患者8例,其中同胞HLA全合4例、单倍型相合4例,移植复发后过继性回输供者来源的体外扩增NK细胞,并在回输后每周留取1次外周血,共5周,检测回输后患者体内NK细胞数量和功能的变化规律,并初步评估NK细胞回输后安全性及临床疗效。结果:8例患者中有4例NK细胞回输治疗后有反应:3例由微小残留病阳性转为阴性,1例髓外复发转阴。免疫学监测显示,治疗有反应病例回输后NK细胞活化型受体NKG2D、NKp30及NKp46表达及CD107a分泌水平较无反应组明显升高。随访至allo-HSCT后5年,3例无白血病长期存活,其余死亡。NK细胞回输安全,未见明显不良反应,5例患者NK细胞回输前存在慢性移植物抗宿主病,NK细胞回输后移植物抗宿主病未加重甚至缓解。结论:初步结果显示,移植后复发或持续微小残留病阳性患者,过继性回输NK细胞治疗后有反应的患者伴有NK细胞活化型受体及功能恢复,无明显不良反应,但疗效和安全性尚需在大样本中进一步证实。Objective:To explore immunological changes and clinical efficacy of adoptive transfer of NK cells in relapsed acute leukaemia patients with no response to donor lymphocyte infusion(DLI)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods:Since February 2011 to January 2014,8 patients underwent allo-HSCT at Peking University Institute of Hematology were selected,and then relapsed post transplantation,4 cases were HLA-compatible and 4 cases were siblings HLA haplotype.All of them adopted adoptive transfer expanded NK cells from healthy donors after relapse and peripheral blood was collected once a week after adoptive therapy for a total of 5 weeks. After transfer,number and function of NK cells in patients were detected,safety and clinical efficacy after adoptive NK therapy were evaluated.Results:Among 8 patients,4 patients responded:3 patients turned from positive minimal residual disease to negative and 1 patient with extra-medullary relapse turned negative. Immunological monitoring showed that expressions of activating NK cell receptors such as NKG2D,NKp30 and NKp46 and secretion of CD107a were significantly higher in treatment-responsive cases after therapy than in non-responsive group. Long term follow-up showed that 3 patients survived without leukemia for over 5 years,however,the rest died. Adoptive transfer of NK cells was safe and no obvious adverse reactions were observed. Five patients had active graft-versus-host disease before treatment while graft-versus-host disease was relieved after NK cell infusion.Conclusion:Preliminary results showed that treatment-responsive cases after adoptive NK cell transfer were accompanied by activated receptors and functional recovery of NK cells in patients with relapse or persistent minimal residual disease after transplantation and without obvious adverse reactions. In addition,efficacy and safety of adoptive transfer of NK cells are still need to be further confirmed in a large sample size.

关 键 词：白血病 复发 过继性回输 NK细胞 

分 类 号：R459.9[医药卫生—治疗学]