炎症细胞因子在嵌合抗原受体-T细胞治疗中的监测价值  

The monitoring value of twelve inflammatory cytokines in chimeric antigen receptor T cell immunotherapy

作　　者：朱莉颖 陈肖 时雨 赵四书 金慧敏 王琰[1] 李建勇[1] 吴雨洁[1] Zhu Liying;Chen Xiao;Shi Yu;Zhao Sishu;Jin Huimin;Wang Yan;Li Jianyong;Wu Yujie(Department of Hematology,the First Affiliated Hospital of Nanjing Medical University Jiangsu Provincial People Hospital,Nanjing 210029,China)

机构地区：[1]南京医科大学第一附属医院,江苏省人民医院血液科,南京210029

出　　处：《中华检验医学杂志》2022年第8期840-845,共6页Chinese Journal of Laboratory Medicine

基　　金：国家自然科学基金项目(81370656);江苏省六大人才高峰项目(2014-WSN-009)。

摘　　要：目的探讨恶性血液病患者接受嵌合抗原受体(CAR)-T细胞免疫治疗后,12种炎症细胞因子表达水平对细胞因子释放综合征(CRS)的早期发现和指导治疗的重要意义。方法选择2017年至2020年南京医科大学第一附属医院采用CAR-T细胞免疫治疗的住院患者12例,包括男性6例,女性6例,年龄53.0(49.8,62.5)岁。12例CAR-T细胞免疫治疗患者细胞回输后,采用流式细胞微球技术在不同时间点检测血清白细胞介素(IL)-1β、IL-2、IL-4、IL-5、IL-6、IL-8、IL-10、IL-12P70、IL-17A、干扰素(IFN)-α、IFN-γ和肿瘤坏死因子(TNF)-α水平,对比分析同期的C反应蛋白(CRP)、D二聚体(D-D)、血清铁蛋白(SF)和乳酸脱氢酶(LDH)。根据CRS诊断标准进行分级(包括0、1、2和3级),比较4组间的差异。采用Spearman相关系数对炎症细胞因子表达水平和CRS分级进行相关性分析。绘制受试者工作特征(ROC)曲线,确定炎症细胞因子预测CRS的敏感度、特异度。结果12例患者CAR-T细胞回输后分别在第1、4、7、11天进行CRS分级,总计48例次(包括CRS 0级25例,CRS 1级6例,CRS 2级9例,CRS 3级8例),经相关性分析显示,IL-4、IL-6、IL-10、TNF-α、IFN-γ、IL-1β、IL-8的表达水平与CRS分级呈正相关性(P<0.05),相关系数分别为0.384、0.730、0.632、0.341、0.681、0.319、0.622。在12例患者中出现升高的7种炎症细胞因子(IL-6、IL-10、IFN-γ、IL-8、IL-2、TNF-α和IFN-α),开始升高的时间平均值分别为3.4、5.3、6.1、2.9、4.3、6.0和5.8 d,CRP、D-D、SF和LDH开始升高的时间平均值为6.6、7.6、8.3和7.6 d。出现升高的7种炎症细胞因子开始升高的时间平均值均小于CRP、D-D、SF和LDH。有效治疗后,除IL-6外,其余6种炎症细胞因子(IL-10、IFN-γ、IL-8、IL-2、TNF-α和IFN-α)转归时间平均值分别为7.8、3.9、5.1、8.0、6.0、2.5 d,均小于CRP、D-D、SF和LDH的转归时间平均值9.7、9.2、13.7和13.8 d。ROC曲线显示,IL-6、IL-10、IFN-γ和IL-8对CRObjective To investigate the significance of 12 inflammatory cytokines in early detection and treatment guidance of hematologic malignant patients with Cytokine release syndrome(CRS)after Chimeric antigen receptor(CAR)-T cell immunotherapy.Methods A total of 12 patients,including 6 males and 6 females,aged 53.0(49.8,62.5)years old,were treated with CAR-T cell immunotherapy in the First Affiliated Hospital of Nanjing Medical University from 2017 to 2020.Cytometric bead array was used to detect the serum levels of IL-1β,IL-2,IL-4,IL-5,IL-6,IL-8,IL-10,IL-12P70,IL-17A,IFN-α,IFN-γ,and TNF-αat different time points after cell infusion in all patients receiving CAR-T cell immunotherapy.C-reactive protein(CRP),D-dimer(D-D),serum ferritin(SF),and lactate dehydrogenase(LDH)were measured at the corresponding period.CRS was classified into four grades according to the diagnostic criteria,from 0 to 3.The differences of the above mentioned parameters between the four groups were compared.The Speedman correlation coefficient was used to analyze the correlation between inflammatory cytokine expression levels and CRS grades.Plot the subject′s receiver operating characterist(ROC)curve to determine the sensitivity and specificity of inflammatory cytokines to predict CRS.Results CRS grading was performed on day 1,4,7,and 11 after CAR-T cell infusion in 12 patients.There are 48 cases in total,including 25 cases of CRS grade 0,6 cases of CRS grade 1,9 cases of CRS grade 2,and 8 cases of CRS grade 3.The correlation analysis of 48 cases showed that the expression levels of IL-4,IL-6,IL-10,TNF-α,IFN-γ,IL-1β,and IL-8 were positively correlated with CRS grade(P<0.05).The correlation coefficients were 0.384,0.730,0.632,0.341,0.681,0.319,and 0.622,respectively.7 inflammatory cytokines(IL-6,IL-10,IFN-γ,IL-8,IL-2,TNF-α,and IFN-α)were elevated in 12 patients,and the average time to start the rise was 3.4,5.3,6.1,2.9,4.3,6.0 and 5.8 days,respectively.The time for CRP,D-D,SF,and LDH to begin to rise were 6.6,7.6,8.3 and 7.6 days,which

关 键 词：炎症趋化因子类 嵌合抗原受体T细胞 流式微球技术 细胞因子释放综合征 

分 类 号：R730.51[医药卫生—肿瘤]