在缺乏细胞表面癌特异性抗原的情况下，免疫疗法（如嵌合抗原受体（CAR）T细胞、单克隆抗体或双特异性T细胞促动剂）通常会针对谱系抗原。目前，此类免疫疗法是根据每种疾病分别设计和测试的。这种方法效率低下，并且仅限于少数临床可耐受的谱系抗原。因此，我们试图开发一种针对全白细胞标记物CD45的通用CAR T细胞疗法，用于治疗血液癌症。为了保护健康的造血系统细胞（包括CAR T细胞）免受CD45引发的靶向损伤而同时保留CD45的基本功能，我们确定了CAR所靶向的CD45表位，并通过CRISPR腺嘌呤碱基编辑来实现一个能够规避CAR T细胞识别的保持功能的突变。经过表位编辑的CD45 CAR T 细胞对自身溶杀免疫并对患者来源的急性髓系白血病、B细胞淋巴瘤和急性T细胞白血病具有疗效。经过表位编辑的造血干细胞（HSCs）受到CAR T细胞的保护，并且与CD45基因缺失细胞不同，它们可以在体内植入、存活和分化。在HSCs和T细胞中进行体外表位编辑可安全且有效地使用CD45 CAR-T细胞和双特异性T细胞促动剂治疗血液恶性肿瘤，并可以用于其他需要进行强烈造血系统消除的疾病治疗中。

In the absence of cell-surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell engagers typically target lineage antigens. Currently, such immunotherapies are individually designed and tested for each disease. This approach is inefficient and limited to a few lineage antigens for which the on-target/off-tumor toxicities are clinically tolerated. Here, we sought to develop a universal CAR T cell therapy for blood cancers directed against the pan-leukocyte marker CD45. To protect healthy hematopoietic cells, including CAR T cells, from CD45-directed on-target/off-tumor toxicity while preserving the essential functions of CD45, we mapped the epitope on CD45 that is targeted by the CAR and used CRISPR adenine base-editing to install a function-preserving mutation sufficient to evade CAR T cell recognition. Epitope edited CD45 CAR T cell were fratricide-resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. Epitope edited hematopoietic stem cells (HSCs) were protected from CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo. Ex vivo epitope editing in HSCs and T cells enables the safe and effective use of CD45-directed CAR-T cells and bispecific T cell engagers for the universal treatment of hematologic malignancies and might be exploited for other diseases requiring intensive hematopoietic ablation.