【《Nature》——急性髓性白血病候选治疗方式：供体HSPCs的表位编辑】

当非肿瘤靶向毒性是急性髓系白血病免疫疗法成功完成临床转化的关键限制因素时，HSPCs表位编辑可以实现更安全、更有效的免疫治疗。

【题目】 表位编辑使急性髓系白血病的靶向免疫治疗成为可能

【摘要】 尽管靶向造血非必需谱系抗原（如急性淋巴细胞白血病中B细胞的CD19）观察到了非常好的疗效，但由于缺乏肿瘤限制性抗原，过继性免疫疗法的广泛适用性受到了阻碍。急性髓系白血病免疫疗法以造血干细胞/祖细胞（HSPCs）或分化的髓系细胞表达的基因为靶标，会产生难以承受的非肿瘤靶向毒性。在本研究中，我们发现对用于骨髓移植的供体HSPCs进行表位工程学处理，使造血细胞系对嵌合抗原受体（CAR）T细胞或单克隆抗体具有选择性免疫力，而不影响蛋白质功能或调控。这种策略可以靶向白血病存活所必需的基因（无论这些基因在造血干细胞上是否有共同表达），从而降低肿瘤免疫逃逸的风险。通过进行表位定位和文库筛选，我们确定了能消除靶向III类受体酪氨酸激酶FLT3、KIT以及IL-3受体CD123的治疗性单克隆抗体结合力的氨基酸突变，并优化了碱基编辑方法，将其引入CD34+ HSPCs，使其保持长期移植和多线分化能力。经过CAR T细胞治疗后，我们证实了表位编辑造血细胞的抗药性，并同时根除了源自患者的急性髓性白血病异种移植物。此外，我们还表明，HSPCs的多重表位工程是可行的，并且能够针对多个靶点进行更有效的免疫治疗，而不会产生多重的肿瘤脱靶毒性。我们预想这种方法将为治疗复发/难治性急性髓性白血病提供机会，并实现更安全的非遗传毒性条件。

英文原文

[Report] Epitope editing of HSPCs can enable safer and more effective immunotherapies when on-target/off-tumour toxicities are the key limiting factor to successful completion of clinical translation of acute myeloid leukaemia immunotherapies.

[Title] Epitope editing enables targeted immunotherapy of acute myeloid leukaemia

[Authors] Gabriele Casirati, Andrea Cosentino, Adele Mucci, Mohammed Salah Mahmoud, Iratxe Ugarte Zabala, Jing Zeng, Scott B. Ficarro, Denise Klatt, Christian Brendel, Alessandro Rambaldi, Jerome Ritz, Jarrod A. Marto, Danilo Pellin, Daniel E. Bauer, Scott A. Armstrong & Pietro Genovese

[Abstract] Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.

原文链接

http://t.cn/A6Oa3VdN