急性B淋巴细胞白血病嵌合抗原受体-T细胞免疫治疗后血清细胞因子水平与桥接异基因造血干细胞移植预后的相关研究  

Study on the relationship between serum cytokines levels after chimeric antigen receptor (CAR)-T cell immunotherapy and the prognosis of bridged allogeneic hematopoietic stem cell transplantation in acute B lymphoblastic leukemia patients

作　　者：欧晓琪 陈曼 赵玮 张改玲 傅旻婧 王东出 邱丽媛 王榕 蒋能刚[1] 樊吉文 张弦 李壹[1] 王卉 Ou Xiaoqi;Chen Man;Zhao Wei;Zhang Gailing;Fu Minjing;Wang Dongchu;Qiu Liyuan;Wang Rong;Jiang Nenggang;Fan Jiwen;Zhang Xian;Li Yi;Wang Hui(Department of Laboratory Medicine,West China Hospital,Sichuan University,Chengdu 610041,China;Department of Laboratory Medicine,Heibei Yanda Ludaopei Hospital,Langfang 065201,China;Department of Transplantation,Beijing Ludaopei Hospital,Beijing 100176,China;Department of Hematology,Heibei Yanda Ludaopei Hospital,Langfang 065201,China;Department of Case and Medical Laboratory,Beijing Ludaopei Hospital,Beijing 100176,China;Department of Clinical Microbiology and Immunology,School of Laboratory Medicine,Guizhou Medical University,Guiyang 550000,China)

机构地区：[1]四川大学华西医院实验医学科,成都610041 [2]河北燕达陆道培医院检验科,廊坊065201 [3]北京陆道培医院移植科,北京100176 [4]河北燕达陆道培医院血液科,廊坊065201 [5]北京陆道培医院病例与医学检验科,北京100176 [6]贵州医科大学检验医学院临床微生物与免疫学教研室,贵阳550000

出　　处：《中华检验医学杂志》2023年第5期493-500,共8页Chinese Journal of Laboratory Medicine

基　　金：河北省科技厅青年基金(20211035);四川省科技厅重点研发项目(2021YFS0160);河北省医学科学研究课题(20220963)。

摘　　要：目的研究急性B淋巴细胞白血病(B-ALL)患者接受嵌合抗原受体(CAR)-T细胞免疫治疗后血清细胞因子和趋化因子水平与其桥接异基因造血干细胞移植术(allo-HSCT)后发生早期急性移植物抗宿主病(aGVHD)及血清细胞因子和趋化因子水平与患者预后关系。方法根据病例对照原则纳入2019年9月18日至2022年5月9日于河北燕达陆道培医院接受CD19-CAR-T细胞免疫治疗且后续均进行allo-HSCT的42例B-ALL患者为研究对象, 采用Mann-WhitneyU检验比较同一时间点不同患者CAR-T细胞免疫治疗后到桥接移植期间aGVHD相关细胞因子以及趋化因子的水平变化, 观测时间点为接受CAR-T治疗前当天, 以及接受CAR-T治疗到桥接移植之间的时间点:接受CAR-T细胞治疗后第4、7、14、21、28天。绘制受试者工作特征(ROC)曲线评估细胞因子及趋化因子预测患者发生aGVHD及aGVHD患者发生死亡的预测价值。采用 Kaplan-Meier法和Log-rank检验进行生存分析。结果入组42例患者, 24例发生aGVHD, 其中11例死于aGVHD, 31例患者存活。接受CAR-T细胞治疗前当天aGVHD组与无aGVHD组患者细胞因子及趋化因子比较, 差异无统计学意义(P>0.05)。第21天时, aGVHD组患者血清弹性蛋白酶特异性抑制剂(Elafin)水平为4 482(2 811, 6 061)ng/L, 较无aGVHD组患者的2 466(1 948, 3 375)ng/L高(Z=3.145, P=0.001);第28天时aGVHD组患者血清Elafin水平为4 391(2 808, 5 594)ng/L, 高于无aGVHD组的2 463(1 658, 2 830)ng/L(Z=2.038, P=0.048)。在第14天时, aGVHD死亡组与aGVHD生存组比较, 血清巨噬细胞炎症蛋白1α(MIP-1α)[21.02(12.36, 30.35)ng/L比5.56(3.64, 10.79)ng/L]、可溶性CD25(sCD25)[422.47(257.99, 1 233.78)IU/ml比 216.11(133.75, 457.39)IU/ml]、Elafin[4 101(2 393, 5 006)ng/L比 2 155(1 781, 3 033)ng/L]、白细胞介素(IL)-6[119.08(23.97, 183.43)ng/L比8.39(2.91, 17.42)ng/L]、IL-8[13.56(12.50, 24.52)ng/L比2.83(1.73, 6.87)ng/L]更高(Z=2.653, P=0.007;Z=2.176, P=0.030;Z=2.058, P=0.041;Z=3.329, Objective To investigate the relationship between the levels of serum cytokines and chemokines and the prognosis of patients with acute B-ALL after receiving chimeric antigen receptor(CAR)-T cell immunotherapy and acute graft-versus-host disease(aGVHD)in patients after bridging allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods According to the case-control principle,Forty-two patients with B-ALL who received CD19-CAR-T cell immunotherapy bridged to allo-HSCT at Heibei Yanda Ludaopei Hospital from September 18,2019 to May 9,2022 were enrolled.Mann-Whitney U test was used to compare the changes of aGVHD-related cytokines and chemokine levels between CAR-T cell immunotherapy and bridging transplantation in different patients at the same time.Their plasma levels of cytokines and chemokines related to aGVHD were monitored at the day before CAR-T therapy and after CAR-T treatment at day 4,7,14,21,28.The receiver operating characteristic curve was drawn to evaluate the predictive value of cytokines and chemokines in predicting the occurrence and the death of aGVHD patients.Kaplan-Meier method and Log-rank tests were used for Overall survival(OS)analysis.Results Twenty-four of total 42 patients had aGVHD,of which 11 patients died and 31 patients survived.There was no significant difference in cytokines and chemokines between the aGVHD group and the non-aGVHD group on the day before CAR-T cell treatment.According to statistical analysis,the serum Elafin levels of aGVHD group was higher than that of non-aGVHD group at the 21st day[4482(2811,6061)ng/L vs 2466(1948,3375)ng/L,Z=3.145,P=0.001]and the 28st day[4391(2808,5594)ng/L vs 2463(1658,2830)ng/L,Z=2.038,P=0.048]separately.At the 14th day,serum cytokines and chemokines levels between the two group were as follows,MIP-1α[21.02(12.36,30.35)ng/L vs 5.56(3.64,10.79)ng/L],sCD25[422.47(257.99,1233.78)IU/ml vs 216.11(133.75,457.39)IU/ml],Elafin[4101(2393,5006)ng/L vs 2155(1781,3033)ng/L],IL-6[119.08(23.97,183.43)ng/L vs 8.39(2.91,17.42)ng/L]and IL-8[13.56(12

关 键 词：嵌合抗原受体T细胞治疗 急性B淋巴细胞白血病 急性移植物抗宿主病 弹性蛋白酶抑制因子 白细胞介素6 白细胞介素8 白细胞介素2受体α亚单位 趋化因子CCL3 

分 类 号：R733.71[医药卫生—肿瘤]