肿瘤细胞治疗研究
英文原题：Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity.
我们的数据支持 CAR-T 治疗前全身性炎症与 ICANS 相关的观点。
背景：复发/难治性B细胞淋巴瘤（BCL）患者输注第二代自体CD19靶向嵌合抗原受体（CAR）T细胞后，可能发生免疫效应细胞相关神经毒性综合征（ICANS）等炎症并发症。现有文献提示，CAR-T输注前的免疫特征可能影响ICANS发生概率。方法：本单中心前瞻性研究纳入53名复发/难治性BCL患者，接受已获批CAR T细胞产品治疗（29名axi-cel，24名tisa-cel）。研究在淋巴细胞清除前（pre-LD）分析临床、生化和血液学指标。在21名有新鲜外周血样本的患者亚组中，进行了白细胞和细胞外囊泡（EV）流式分析。此外，研究测定了一组可溶性血浆生物标志物（IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL）和微RNA（miR-146a-5p、miR-21-5p、miR-126-3p、miR-150-5p），这些指标与细胞衰老和炎症相关。结果：在整个队列（n=53）pre-LD时间点进行多变量分析显示，CD3⁺CD8⁺淋巴细胞比例较低（38.6%对46.8%；OR=0.937，95%置信区间0.882–0.996，p=0.035）以及血清C反应蛋白（CRP）水平较高（4.52 mg/dL对1.00 mg/dL；OR=7.133，95%置信区间1.796–28，p=0.005）与ICANS相关。在21名患者的pre-LD样本中，ICANS患者CD8⁺CD45RA⁺CD57⁺衰老细胞比例显著升高（中位数16.50%对9.10%，p=0.009），单核髓源性抑制细胞（M-MDSC）比例也升高（中位数4.4%对1.8%，p=0.020）。这些患者携带CD14⁺和CD45⁺髓系标志物的EV、髓系趋化因子CXCL-9以及MDSC分泌的细胞因子IL-10水平均增加。值得注意的是，血清循环神经丝轻链（一种神经轴索损伤标志物）水平与衰老CD8⁺ T细胞、M-MDSC、IL-10和CXCL-9水平呈正相关。ICANS患者与非ICANS患者之间，所选微RNA水平未见变化。讨论：我们的数据支持CAR-T治疗前全身炎症与ICANS相关这一观点。pre-LD时间点衰老CD8⁺ T细胞和M-MDSC比例较高，与神经轴索损伤早期迹象相关，提示ICANS可能是一个在CAR-T输注前已开始过程的最终表现，该过程与患者既往临床经历有关。
BACKGROUND: Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS. METHODS: This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation. RESULTS: Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3 + CD8 + lymphocytes (38.6 % vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8 + CD45RA + CD57 + senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14 + and CD45 + myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8 + T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients. DISCUSSION: Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8 + T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.
MEMBER ACCOUNT
登录成功会直接打开下一页。
