系统性红斑狼疮CAR T细胞治疗疗效预测及安全性评估的潜在生物标志物
Potential biomarkers for prediction of the efficacy and safety of CAR T cell treatment in systemic lupus erythema-tosus
王一阳 1吕良敬1
作者信息
- 1. 上海交通大学医学院附属仁济医院风湿科,上海 200001
- 折叠
摘要
系统性红斑狼疮(systemic lupus erythematosus,SLE)是一种复杂的自身免疫疾病,传统治疗在部分重度和难治性患者中效果有限.近期研究显示,嵌合抗原受体(chimeric antigen receptor,CAR)T细胞疗法在SLE治疗中展现出了具有前景的疗效.生物标志物在精准评估治疗效果和安全性方面至关重要,CAR T细胞治疗与安全性评估标志物包括传统标志物和与CAR T细胞疗法相关的标志物.传统的SLE病情监测标志物,仍可用于CAR T细胞治疗基线随访和病情监测,如血清抗双链DNA、抗单链DNA和抗核小体等自身抗体的滴度下降,血清补体水平恢复正常,以及尿蛋白/肌酐比值的改善,均提示病情得到有效控制.CAR T细胞疗效监测标志物分为B细胞和T细胞标志物.输注后,B细胞数量下降,B细胞表型以初始B细胞为主,记忆B细胞和浆母细胞的比例显著降低,表明治疗取得了疗效.输注前,初始T细胞(CD45RA+CD27+)和中央记忆型T细胞(CD45RA-CD62L+CD27+)的高比例则提示更强的抗肿瘤效应;患者的CAR T细胞表达与早期记忆分化相关的转录因子,如T细胞因子7和淋巴增强子结合因子1,提示这些患者对CAR T细胞疗法更为敏感.输注后,CD25、CD69和CD137等T细胞激活标志物,以及CD57、PD-1和Tim-3等耗竭标志物的高表达,提示T细胞的杀伤能力受到限制.CAR T细胞治疗安全性标志物不仅包括CAR T细胞分泌的效应细胞因子(如白细胞介素-2和IFN-γ),还包括单核细胞和巨噬细胞产生的细胞因子(如IL-1和IL-8),其水平可用于评估CAR T细胞疗法最常见的毒副反应[细胞因子释放综合征(cytokine release syn-drome,CRS)和免疫效应细胞相关神经毒性综合征(immune effector cell-associated neurotoxicity syndrome,ICANS)].高水平的血清巨噬细胞炎性蛋白1α对于预测CAR T细胞治疗后发生严重CRS和ICANS的风险具有较高的价值.此外,基线血小板计数和中性粒细胞绝对值可预测血液毒性,由IL-8、IFN-γ和IL-1β组成的感染相关预测模型,能够有效预测患者输注后出现严重感染的风险.CAR受体结构设计、清除淋巴细胞的化疗方式,患者曾接受的治疗选择及自身免疫状态等都会影响CAR T细胞治疗的疗效及安全性.在当前及未来将开启的相关临床研究中,应纳入全面、规范的检测和评估体系,为CAR T细胞疗法在SLE等自身免疫疾病的应用,提供比较标准.
Abstract
Systemic lupus erythematosus(SLE)is a complex autoimmune disease for which traditional treatments of-ten show limited efficacy in severe and refractory cases.Recently,chimeric antigen receptor(CAR)T cell therapy has emerged as a novel immunotherapy strategy,demonstrating significant efficacy in preliminary studies for SLE treatment.Biomarkers are crucial for the precise assessment of treatment efficacy and safety.Biomarkers for monitoring the efficacy of CAR T cell therapy include traditional markers and markers related to CAR T therapy.Traditional markers for SLE disease monitoring,such as decreased titers of serum anti-double-stranded DNA,anti-single-stranded DNA,anti-nucleosome auto-antibodies,normalization of serum complement levels,and improvement of urine protein/creatinine ratio,indicate that the disease is effectively controlled and can still be used for baseline follow-up and disease monitoring during CAR T cell therapy.B cell markers indicating effective CAR T therapy include a decrease in the number of B cells after infusion,a B cell phenotype dominated by the naive B cell,and a significant decrease in the proportion of memory B cells and plasma-blasts.Regarding T cell markers related to CAR T therapy,the high proportion of naive T cell(CD45RA+CD27+)and cen-tral memory T cell(CD45RA-CD62L+CD27+)subsets before infusion indicate stronger anti-tumor efficacy;The initial ex-pression of transcription factors associated with early memory differentiation on patients'CAR T cells,such as T cell factor 7(TCF7)and lymphoid enhancer-binding factor 1(LEF1),suggest that these patients may be sensitive to CAR T therapy.After infusion,high expression of T cell activation markers(CD25,CD69 and CD137),and exhaustion markers(CD57,PD-1,and Tim-3)indicate that T cells are in a state of dysfunction,with limited expansion,cytokine secretion and cell killing capabilities.Safety markers,including effector cytokines secreted by CAR T cells[interleukin(IL)-2 and IFN-γ]and cyto-kines produced by monocytes and macrophages(IL-1 and IL-8),can be used to monitor the most common toxicities and side-effects of CAR T-cell therapies,cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syn-drome(ICANS).High levels of serum macrophage inflammatory protein-1α(MIP-1α)are of high value for predicting the risk of severe CRS and ICANS after CAR T-cell therapy.In addition,haematotoxicity markers include baseline platelet count and absolute neutrophil count,and an infection-related prediction model consisting of IL-8,IFN-γ and IL-1β are effective in predicting the risk of severe infection in patients after infusion.The design of the CAR receptor structure,the chemothera-peutic modality used to remove the lymphocytes,as well as the choice of treatments that the patient had received and the au-toimmune status,all affect the efficacy and safety.A comprehensive and standardised testing and evaluation system should be included in current and future clinical studies to provide a comparative standard for the use of CAR T-cell therapy in au-toimmune diseases such as SLE.
关键词
系统性红斑狼疮/CAR/T细胞疗法/生物标志物Key words
Systemic lupus erythematosus/Chimeric antigen receptor T cell therapy/Biomarkers引用本文复制引用
基金项目
国家重点基础研究发展计划(973计划)(2022YFC2504601)
国家自然科学基金面上项目(81974251)
上海交通大学"交大之星"计划医工交叉研究基金重点项目(YG2023ZD09)
出版年
2024
国家科技期刊平台
NSTL
万方数据