Department of Pediatric Medicine, Division of Critical Care, St. Jude Children's Research Hospital, Memphis, Tennessee.
Pediatric Hematology and Oncology, Seattle Children's Hospital and the University of Washington School of Medicine, Seattle, Washington.
Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. doi: 10.1016/j.jtct.2023.03.006. Epub 2023 Mar 9.
T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.
T 细胞介导的过度炎症反应,如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),现已成为嵌合抗原受体 (CAR) T 细胞治疗的明确毒性。然而,随着 CAR T 细胞领域的发展,人们越来越认识到,CAR T 细胞输注后出现噬血细胞性淋巴组织细胞增生症 (HLH) 样毒性在广泛的患者人群和 CAR T 细胞构建体中都有发生。重要的是,这些 HLH 样毒性与最初描述的 CRS 及其严重程度并不直接相关。这种新出现的毒性,尽管定义不明确,但与危及生命的并发症有关,因此迫切需要改进识别和最佳管理。为了改善患者的预后并构建一个框架来描述和研究这种 HLH 样综合征,我们成立了一个由原发性和继发性 HLH、儿科和成人 HLH、传染病、风湿病和血液学、肿瘤学和细胞治疗方面的专家组成的美国移植和细胞治疗学会小组。通过这项努力,我们提供了经典原发性和继发性 HLH 的基础生物学概述,探讨了其与 CAR T 细胞输注后类似表现的关系,并提出了“免疫效应细胞相关 HLH 样综合征 (IEC-HS)”这一术语来描述这种新出现的毒性。我们还描述了识别 IEC-HS 的框架,并提出了一个分级方案,可用于评估严重程度并促进跨试验比较。此外,鉴于患者出现 IEC-HS 时优化结局的迫切需要,我们提供了对潜在治疗方法的深入了解和优化支持性护理的策略,并描述了在出现 IEC-HS 的患者中应考虑的替代病因。通过将 IEC-HS 集体定义为一种过度炎症毒性,我们现在可以进一步研究这种毒性特征的病理生理学,并朝着更全面的评估和治疗方法迈进。
Transplant Cell Ther. 2023-7
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