Tian Gengwen, Courtney Amy N, Yu Hangjin, Bhar Saleh, Xu Xin, Barragán Gabriel A, Martinez Amador Claudia, Ghatwai Nisha, Wood Michael S, Schady Deborah, Montalbano Antonino, Reddy Shantan, Roche Aoife M, de la Cerda David, Parsons Donald Williams, Di Pierro Erica J, Bushman Frederic D, Heczey Andras, Metelitsa Leonid S
Center for Advanced Innate Cell Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA.
J Immunother Cancer. 2025 Jan 11;13(1):e010156. doi: 10.1136/jitc-2024-010156.
The ability of immune cells to expand numerically after infusion distinguishes adoptive immunotherapies from traditional drugs, providing unique therapeutic advantages as well as the potential for unmanageable toxicities. Here, we describe a case of lethal hyperleukocytosis in a patient with neuroblastoma treated on phase 1 clinical trial (NCT03294954) with autologous natural killer T cells (NKTs) expressing a GD2-specific chimeric antigen receptor and cytokine interleukin 15 (GD2-CAR.15). This patient was the first to be treated on dose level (DL) 5 and the first patient whose product was restimulated with K562-derived artificial antigen-presenting cells (aAPCs) instead of autologous peripheral blood mononuclear cells (PBMCs). 12 previously treated patients on DLs 1 through 4 did not experience significant toxicity. Our root-cause analysis revealed no genetic alterations of known clinical significance and excluded the possibility of clonal expansion due to insertional retroviral mutagenesis. We report that the use of aAPCs instead of PBMCs for CAR-NKT restimulation contributed to a hyperproliferative state associated with distinct gene expression that possibly led to explosive lymphocyte expansion and uncontrolled toxicity in the patient. These findings warrant the implementation of measures to control immune cell activation during manufacture of cell therapy products, especially those armed with transgenic cytokines.
免疫细胞在输注后进行数量扩增的能力，使过继性免疫疗法有别于传统药物，这既带来了独特的治疗优势，也存在产生难以控制的毒性的可能性。在此，我们描述了1例在1期临床试验（NCT03294954）中接受治疗的神经母细胞瘤患者发生致死性高白细胞血症的病例，该患者接受了表达GD2特异性嵌合抗原受体和细胞因子白细胞介素15（GD2-CAR.15）的自体自然杀伤T细胞（NKT）治疗。该患者是首个接受5级剂量水平（DL）治疗的患者，也是首个其产品用源自K562的人工抗原呈递细胞（aAPC）而非自体外周血单核细胞（PBMC）进行再刺激的患者。之前接受1至4级剂量水平治疗的12例患者未出现明显毒性。我们的根本原因分析未发现具有已知临床意义的基因改变，并排除了由于插入性逆转录病毒诱变导致克隆扩增的可能性。我们报告称，使用aAPC而非PBMC对CAR-NKT进行再刺激导致了一种与独特基因表达相关的过度增殖状态，这可能导致了该患者淋巴细胞的爆发性扩增和无法控制的毒性。这些发现促使我们在细胞治疗产品的制造过程中采取措施来控制免疫细胞的激活，尤其是那些配备转基因细胞因子的产品。
