活化自体淋巴细胞过继性免疫治疗在原发性肝细胞癌中的疗效观察  

Observation on the effect of adoptive immunotherapy with activated autologous lymphocytes in the treatment of primary hepatocellular carcinoma

作　　者：杨岩丽 廖丽 张婧 孙鹏 高岛健一 张凤春 杨玉惠 张斌 胡亮钉 YANG Yanli;LIAO Li;ZHANG Jing;SUN Peng;TAKASHIMA Kenichi;ZHANG Fengchun;YANG Yuhui;ZHANG Bin;HU Liangding(Department of Hematopoietic Stem Cell Transplantation,the Fifth Medical Center of Chinese PLA General Hospital,Beijing 100071,China;Beijing Kand’s Science and Technology Development Co.,Ltd.,Beijing Longbao Technology Development Co.,Ltd.,Beijing 100176,China)

机构地区：[1]中国人民解放军总医院第五医学中心造血干细胞移植科,北京100071 [2]北京龙宝科技集团北京康达行健科技发展有限公司,北京100176

出　　处：《中国肿瘤生物治疗杂志》2021年第11期1098-1106,共9页Chinese Journal of Cancer Biotherapy

基　　金：军队后勤科研重大项目资助(No.AWS17J010)。

摘　　要：目的:评价活化自体淋巴细胞过继性免疫治疗(adoptive immunotherapy,AIT)是否有助于改善原发性肝细胞癌的临床疗效。方法:选取2016年8月至2018年12月在中国人民解放军总医院第五医学中心确诊的64例原发性肝细胞癌患者,通过分层随机法分为免疫治疗组(n=29)和对照组(n=35)。免疫治疗组患者取60 ml外周血分离制备单个核细胞并在含OKT-3和IL-2的培养基中活化培养,回输前进行质控检测。免疫治疗组中的Ⅰ-Ⅲ期患者(n=14)于一线治疗后接受自体淋巴细胞输注(3个月内输注6次),Ⅳ期患者(n=15)仅接受自体淋巴细胞输注;对照组患者接受肝细胞癌相关的其他治疗。疗效评估的主要终点是2年无复发生存(relapse-free survival,RFS)率,次要终点为无进展生存期(progression-free survival,PFS)和总生存期(overall survival,OS)。结果:入组患者中位随访时间为2.8年(0.2-4.2年)。免疫治疗组29名患者共接受了167次(计划174次,完成率96%)预定淋巴细胞输注(平均每人次回输9.30×10^(9)个细胞,其中CD3^(+)HLA-DR细胞约占63%),治疗期间未观察到3级或4级不良反应发生。与对照组相比,免疫治疗组患者2年RFS率显著升高(62.1%vs 22.9%,OR=0.181,95%CI:0.06-0.54,P=0.002),中位PFS(28 vs 8个月,P=0.004)和中位OS(38 vs 34个月,P=0.915)均显著延长。在Ⅰ-Ⅲ期患者中,免疫治疗组(n=14)2年RFS率较对照组(n=18)显著升高(92.9%vs 33.3%,OR=0.38,95%CI:0.004-0.368,P=0.005),中位PFS明显延长(38 vs 14.5个月,P=0.005),而两组OS间无显著差异;Ⅳ期患者两组间PFS(P=0.077)及OS(P=0.994)均未见显著差异。结论:活化自体淋巴细胞AIT为安全可行的肝细胞癌辅助性治疗方法,可提高Ⅰ-Ⅲ期肝细胞癌一线治疗后RFS率、延长患者RFS时间,而对进展期肝细胞癌患者的PFS和OS无明显影响。Objective:To evaluate whether adoptive immunotherapy(AIT)with activated autologous lymphocytes helps to improve the clinical efficacy of primary hepatocellular carcinoma.Methods:Sixty-four patients with primary hepatocellular carcinoma diagnosed at the Fifth Medical Center of Chinese PLA General Hospital from August 2016 to December 2018 were enrolled and divided into immunotherapy group(n=29)and control group(n=35)by the stratified randomized sampling method.60 ml of peripheral blood was drawn from each patient in the immunotherapy group to prepare mononuclear cells,which were then activated and cultured in a medium containing OKT-3 and IL-2.A quality control test was done before blood re-transfusion.In the immunotherapy group,patients in stageⅠ-Ⅲ(n=14)received autologous lymphocyte infusion(6 infusions within 3 months)after first-line treatment,while patients in stageⅣ(n=15)only received autologous lymphocyte infusion therapy.Patients in the control group received other hepatocellular carcinoma-related treatments.The primary endpoint of the efficacy evaluation was the 2-year relapse-free survival(RFS),and the secondary endpoints were progression-free survival(PFS)and overall survival(OS).Results:The median follow-up time of the enrolled patients was 2.8 years(0.2-4.2 years).29 patients in the immunotherapy group received a total of 167 scheduled lymphocyte infusions(with an average of 9.30×10^(9) cells per patient,of which CD3^(+)HLA-DR cells accounted for about 63%;174 infusions were planned,with a completion rate of 96%).During the treatment period,no grade 3-4 adverse reactions were observed.Compared with the control group,patients in the immunotherapy group had a significantly increased 2-year RFS rate(62.1%vs 22.9%,OR=0.181,95%CI:0.06-0.54,P=0.002),and the median PFS(28 vs 8 months,P=0.004)and median OS(38 vs 34 months,P=0.915)were significantly prolonged.Among the patients at stageⅠ-Ⅲ,the PFS rate in the immunotherapy group was significantly higher than that in the control group(92.9%vs 33.3%,O

关 键 词：原发性肝细胞癌 活化自体淋巴细胞 过继性免疫治疗 无进展生存期 总生存期 

分 类 号：R735.7[医药卫生—肿瘤] R730.51[医药卫生—临床医学]