肿瘤细胞治疗研究
英文原题：Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia.
为提高精确性，我们优化了先导编辑，使 HSPCs 中的编辑效率从 5.9% 提升至 78.9%。
急性髓系白血病（AML）是一种恶性肿瘤，其特征为造血干细胞和祖细胞（HSPC）分化异常。CAR-T（CAR-T）细胞免疫疗法虽然靶向 AML 细胞，但常因攻击表达相同抗原的正常细胞而引发严重的靶向脱瘤毒性。本研究使用碱基编辑器（BE）和先导编辑器（PE）改造 HSPC 上的 CD123 表位，在保留正常细胞功能的同时，使健康细胞免受 CAR-T 细胞诱导的细胞毒性。尽管 BE 能有效编辑表位，但复杂的旁观者编辑产物令人担忧。为提高精确性，我们优化了先导编辑，将 HSPC 中的编辑效率从 5.9% 提高到 78.9%。表位改造后的细胞能够抵抗 CAR-T 细胞裂解，同时维持正常分化和功能。此外，将经 BE 或 PE 编辑的 HSPC 输注至人源化小鼠后，髓系细胞获得了对 CAR-T 免疫治疗的选择性抵抗。这一结果验证了一种治疗复发性 AML 的概念验证策略。
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.
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