Kadirkamanathan Renuka, Georgiadis Christos, Kloos Arnold, Joshi Akshay, Etuk Annie, Preece Roland, Gough Oliver, Schambach Axel, Sauer Martin, Heuser Michael, Qasim Waseem
UCL Great Ormond Street Institute of Child Health, London, UK.
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Leukemia. 2025 Oct 1. doi: 10.1038/s41375-025-02720-5.
Acute myeloid leukaemia (AML) is often aggressive and life-threatening with limited curative options. Immunotherapies including chimeric antigen receptor (CAR) T-cell approaches are under investigation, but high levels of disease heterogeneity remain a major hurdle to achieving durable responses. Targeting of multiple antigens may ensure complete immunological coverage of leukaemic blast populations, but such antigens are often also present on healthy haematopoietic populations. To address likely aplasia, strategies can be designed to bridge CAR T-cell therapies to allogeneic stem-cell transplantation (allo-SCT), as demonstrated in recent anti-CD7 CAR T-cell studies. Here we report that monotherapy using base edited "universal" donor CAR T cells against CD33, CLL-1, or CD7 delivered inhibition of AML in immunodeficient mice when antigen expression was homogenous, but combined use of BE-CAR33 and BE-CARCLL-1 T cells was required to address heterogenous CLL-1CD33 disease. We also demonstrate that removal of shared CD7 antigens enabled compatibility of BE-CAR33 and BE-CARCLL-1 with BE-CAR7 T cells, including in a patient-derived xenograft (PDX) model of AML. Therapeutic strategies envisage 'pick and mix' applications of base edited "universal" CAR T cells in combination determined by patient-specific antigen profiles. Such approaches also offer the possibility of deep, cell-based, de-bulking and conditioning ahead of allo-SCT and subsequent donor-derived reconstitution.
急性髓系白血病（AML）通常具有侵袭性且危及生命，治疗选择有限。包括嵌合抗原受体（CAR）T细胞疗法在内的免疫疗法正在研究中，但高水平的疾病异质性仍然是实现持久缓解的主要障碍。靶向多种抗原可能确保对白血病母细胞群体的完全免疫覆盖，但这些抗原通常也存在于健康造血细胞群体中。为了解决可能出现的再生障碍，可以设计策略将CAR T细胞疗法与异基因干细胞移植（allo-SCT）相衔接，最近的抗CD7 CAR T细胞研究已证明了这一点。在此，我们报告，当抗原表达均匀时，使用碱基编辑的“通用”供体CAR T细胞针对CD33、CLL-1或CD7进行单药治疗可在免疫缺陷小鼠中抑制AML，但需要联合使用BE-CAR33和BE-CARCLL-1 T细胞来应对异质性CLL-1CD33疾病。我们还证明，去除共享的CD7抗原可使BE-CAR33和BE-CARCLL-1与BE-CAR7 T细胞兼容，包括在AML的患者来源异种移植（PDX）模型中。治疗策略设想根据患者特异性抗原谱确定碱基编辑的“通用”CAR T细胞的“挑选和组合”应用。这些方法还提供了在allo-SCT和随后的供体来源重建之前进行深度、基于细胞的减瘤和预处理的可能性。
