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

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 syndrome,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。

Systemic lupus erythematosus(SLE)is a complex autoimmune disease for which traditional treatments often 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 autoantibodies,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 plasmablasts.Regarding T cell markers related to CAR T therapy,the high proportion of naive T cell(CD45RA+CD27+)and central memory T cell(CD45RA-CD62L+CD27+)subsets before infusion indicate stronger anti-tumor efficacy;The initial expression 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 cytokines 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 syndrome(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-γand IL-1βare effective in predicting the risk of severe infection in patients after infusion.The design of the CAR receptor structure,the chemotherapeutic modality used to remove the lymphocytes,as well as the choice of treatments that the patient had received and the autoimmune 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 autoimmune diseases such as SLE.