Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.

中文翻译：

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表位引物编辑可保护造血细胞免受急性髓性白血病 CD123 免疫治疗的影响


急性髓系白血病 （AML） 是一种恶性癌症，其特征是造血干细胞和祖细胞 （HSPC） 异常分化。虽然嵌合抗原受体 T （CAR-T） 细胞免疫疗法靶向 AML 细胞，但它们通常通过攻击表达相同抗原的正常细胞来诱导严重的靶向/非肿瘤毒性。在这里，我们使用碱基编辑器 （BEs） 和引物编辑器 （PE） 来修饰 HSPC 上 CD123 的表位，保护健康细胞免受 CAR-T 诱导的细胞毒性，同时保持其正常功能。尽管 BE 有效地编辑了表位，但复杂的旁观者产品是一个问题。为了提高精度，我们优化了引物编辑，将 HSPCs 中的编辑效率从 5.9% 提高到 78.9%。此外，注入人源化小鼠中的 BE 或 PE 编辑 HSPC 赋予髓系对 CAR-T 免疫疗法的选择性耐药性，展示了治疗复发性 AML 的概念验证策略。