BE-CAR33（即用型碱基编辑CAR33 T细胞疗法）治疗急性髓系白血病的1期可行性试验
A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia
CAR-T细胞治疗急性髓系白血病（AML）受限于抗原异质性及与正常组织的共享表达，且经多线治疗患者常难以获取自体T细胞。BE-CAR33是一种通用供者来源、经碱基编辑的靶向CD33的CAR-T细胞，通过多重胞苷脱氨精准破坏TRAC、CD52和CD7位点，以预防移植物抗宿主病并抵抗免疫治疗清除。这项开放标签、非随机、单中心1期研究纳入3例儿童复发/难治AML患者，另1例成人通过同情用药接受治疗，在异基因干细胞移植前输注。不良事件包括≤2级细胞因子释放综合征、3级神经毒性、4级血细胞减少和短暂皮疹。2例患者微小残留病灶减少并桥接至移植。虽然主要终点未达到，但这是首次在人体中证明即用型碱基编辑CAR-T细胞策略可行。
为什么推荐给您：碱基编辑通用型CAR-T首次人体试验，属全新基因编辑模态的临床概念验证，虽未达主要终点仍具里程碑意义。
不需要生物学背景，多打比方
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摘要Abstract
Chimeric antigen receptor (CAR) T cell therapy for acute myeloid leukemia (AML) is constrained by antigen heterogeneity and shared expression with healthy compartments, and there are often challenges in obtaining autologous T cells from heavily pretreated patients. To address these challenges, we developed universal donor-derived, base-edited, anti-CD33 CAR T cells (BE-CAR33) that used precise multiplexed cytidine deamination to simultaneously disrupt the TRAC, CD52, and CD7 loci to prevent graft-versus-host disease and evade immunotherapy effects. An open-label, nonrandomized, single-center phase 1 study (ISRCTN14430213) evaluated the safety, feasibility, and activity of BE-CAR33 cell therapy ahead of allogeneic stem cell transplantation (allo-SCT) for patients with AML. Eligible participants were aged less than 16 years with relapsed/refractory AML. Five patients were screened, and three were enrolled; one additional adult received BE-CAR33 through compassionate access. Participants received fludarabine, cyclophosphamide, and alemtuzumab followed by 1.2 to 1.8 × 10^6 BE-CAR33 cells per kilogram. Treatment-emergent adverse events included cytokine release syndrome (grade ≤2), neurotoxicity (grade 3), cytopenias (grade 4), and transient rashes. Two patients demonstrated reduced minimal residual disease and proceeded to allo-SCT. Serial flow cytometry, chimerism quantification, and vector copy number analyses tracked BE-CAR33 T cells until elimination during transplant. Differentially expressed genes included editing signatures and switched from manufacturing-related toward postexpansion effector and exhaustion profiles. Although primary end points were not met, this first-in-human study demonstrated the feasibility of an "off-the-shelf" base-edited CAR T cell approach and informs future multiantigen strategies against AML.