肿瘤细胞治疗研究
英文原题：Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances.
ICANS 的管理正转向精准医学模式。
背景：嵌合抗原受体（CAR）T细胞疗法已改变血液系统恶性肿瘤的治疗格局。然而，免疫效应细胞相关神经毒性综合征（ICANS）仍是一种重要且可能致命的并发症，约影响27%至65%的患者，并使治疗的风险获益平衡面临挑战。正文：本综述总结了ICANS流行病学、病理生理学、诊断和管理方面的最新进展。不同产品的发生率差异显著；与其他靶点及采用4-1BB结构域的产品相比，抗CD19疗法和含CD28结构域的构建体毒性发生率明显更高。其病理生理机制核心是系统性细胞因子释放及直接细胞损伤所驱动的血脑屏障破坏。单核细胞和巨噬细胞是主要效应细胞，可释放白细胞介素-1和粒细胞-巨噬细胞集落刺激因子，进而触发内皮细胞活化及神经炎症。临床表现通常在输注后第一周出现，范围从轻微语言障碍到危及生命的脑水肿。当前管理已从出现症状后控制转向主动策略。基于严重程度的算法指导皮质类固醇和重症监护支持的使用；新兴预防方法，尤其是使用阿那白滞素阻断白细胞介素-1受体，有望在不损害抗肿瘤疗效的情况下减少重度神经毒性。此外，嵌合抗原受体阳性细胞外囊泡等新型生物标志物及可在症状出现前数日预测毒性的机器学习模型，正提升诊断精准度。结论：ICANS管理正转向精准医学模式。通过整合预测性生物标志物、人工智能和新型预防性干预，临床医生能够更好地进行风险分层并及早治疗。未来需聚焦具有工程化安全特征的下一代构建体，以分离治疗效力与神经毒性，最终改善晚期血液系统恶性肿瘤患者的结局。
BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant and potentially lethal complication, affecting approximately 27% to 65% of patients and challenging the therapeutic risk-benefit profile. MAIN BODY: This review synthesizes recent advances in the epidemiology, pathophysiology, diagnosis, and management of ICANS. Incidence varies significantly by product design, with anti-CD19 therapies and CD28-containing constructs demonstrating markedly higher toxicity rates compared to other targets and 4-1BB-based designs. The pathophysiological mechanism centers on blood-brain barrier disruption driven by systemic cytokine release and direct cellular injury. Monocytes and macrophages act as principal effectors, releasing interleukin-1 and granulocyte-macrophage colony-stimulating factor, which trigger endothelial activation and neuroinflammation. Clinical manifestations typically appear within the first week post-infusion, ranging from mild language disturbances to life-threatening cerebral edema. Current management has evolved from reactive symptom control to proactive strategies. Severity-based algorithms guide the use of corticosteroids and intensive care support, while emerging prophylactic approaches, particularly interleukin-1 receptor blockade with anakinra, show promise in reducing severe neurotoxicity without compromising anti-tumor efficacy. Furthermore, diagnostic precision is improving through the use of novel biomarkers, such as chimeric antigen receptor-positive extracellular vesicles, and machine-learning models that predict toxicity days before symptom onset. CONCLUSIONS: The management of ICANS is shifting towards a precision medicine paradigm. By integrating predictive biomarkers, artificial intelligence, and novel prophylactic interventions, clinicians can better stratify risk and implement early treatments. Future research focusing on next-generation constructs with engineered safety features will be essential to decouple therapeutic efficacy from neurotoxicity, ultimately optimizing outcomes for patients with advanced hematologic cancers.
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