Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany.
Department of Hematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
Front Immunol. 2022 Apr 8;13:877477. doi: 10.3389/fimmu.2022.877477. eCollection 2022.
Endothelial dysfunction is associated with two main complications of chimeric antigen receptor T (CAR-T) cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). This study evaluates the Endothelial Activation and Stress Index (EASIX) as a prognostic marker for high-grade CRS and ICANS in patients treated with CD19-directed CAR-T cells.
In this retrospective study, a training cohort of 93 patients from the ZUMA-1 trial and a validation cohort of 121 patients from two independent centers (University Hospital Heidelberg, Charité University Medicine Berlin) were investigated. The primary objective was to assess the predictive capacity of EASIX measured immediately before the start of lymphodepletion (EASIX-pre) for the occurrence of grade ≥3 CRS and/or ICANS. To explore a possible endothelial link, serum levels of endothelial stress markers (angiopoietin-2, suppressor of tumorigenicity-2, soluble thrombomodulin, and interleukin-8) were determined before lymphodepletion and on day 7 after CART infusion in the validation cohort ( = 47).
The prognostic effect of EASIX-pre on grade ≥3 CRS and/or ICANS was significant in the training cohort [OR 2-fold increase 1.72 (1.26-2.46)] and validated in the independent cohort. An EASIX-pre cutoff >4.67 derived from the training cohort associated with a 4.3-fold increased odds ratio of severe CRS/ICANS in the independent cohort. Serum endothelial distress markers measured on day+7 correlated with EASIX-pre and associated with severe complications.
EASIX-pre is a powerful predictor of severe CRS/ICANS after CD19-directed CART therapy and might be used as a basis for risk-adapted prevention strategies.
嵌合抗原受体 T（CAR-T）细胞治疗的两种主要并发症，细胞因子释放综合征（CRS）和免疫效应细胞相关神经毒性综合征（ICANS），与内皮功能障碍有关。本研究评估内皮激活和应激指数（EASIX）作为接受 CD19 定向 CAR-T 细胞治疗的患者发生重度 CRS 和 ICANS 的预后标志物。
在这项回顾性研究中，我们调查了来自 ZUMA-1 试验的 93 例患者的训练队列和来自两个独立中心（海德堡大学医院、柏林夏里特医科大学）的 121 例患者的验证队列。主要目的是评估在淋巴细胞耗竭前即刻测量的 EASIX（EASIX-pre）预测发生≥3 级 CRS 和/或 ICANS 的能力。为了探索可能的内皮联系，在验证队列中（n=47），在淋巴细胞耗竭前和 CAR-T 输注后第 7 天测定内皮应激标志物（血管生成素-2、肿瘤抑制物-2、可溶性血栓调节蛋白和白细胞介素-8）的血清水平。
EASIX-pre 对训练队列中≥3 级 CRS 和/或 ICANS 的预后作用具有显著性（OR 增加 2 倍 1.72（1.26-2.46）），并在独立队列中得到验证。来自训练队列的 EASIX-pre ＞4.67 截点与独立队列中严重 CRS/ICANS 的优势比增加 4.3 倍相关。第+7 天测量的血清内皮应激标志物与 EASIX-pre 相关，与严重并发症相关。
EASIX-pre 是 CD19 定向 CAR-T 治疗后严重 CRS/ICANS 的有力预测指标，可作为风险适应预防策略的基础。
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