Safety and efficacy of CD33-targeted CAR-NK cell therapy for relapsed/refractory AML: preclinical evaluation and phase I trial

作者：Ruihao Huang, Xiaoqi Wang, Hongju Yan, Xu Tan, Yingying Ma, Maihong Wang, Han Xiao, Jia Liu, Li Gao, Lei Gao, Guangjun Jing, Cheng Zhang, Qin Wen, Xi Zhang · 发表于：Experimental Hematology and Oncology · 年份：2025 · DOI：10.1186/s40164-024-00592-6 · 被引用次数：60 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Lymphoma Diagnosis and Treatment

BACKGROUND: Due to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by "off-target" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells. METHODS: The CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy. RESULTS: The CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable...