美国波士顿儿童医院Pietro Genovese研究组发现，表位编辑可实现急性髓性白血病的靶向免疫疗法。2023年8月30日，《自然》杂志在线发表了这一最新研究成果。

研究人员展示了对用于骨髓移植的供体造血干细胞/祖细胞（HSPC）进行表位工程化处理，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抵抗力，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，而不管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。通过进行表位图谱绘制和文库筛选，研究人员确定了能削弱靶向FLT3、CD123和KIT的治疗性单克隆抗体结合力的氨基酸变化，并优化了碱基编辑方法，将其引入CD34⁺ HSPC，使其保持长期移植和多线分化能力。

经过CAR T细胞治疗后，研究人员证实了表位编辑造血的抗药性，并同时根除了患者衍生的急性髓性白血病异种移植物。此外，研究人员还表明，HSPC的多重表位工程化是可行的，它能针对多个靶点进行更有效的免疫治疗，而不会产生重叠的瘤外毒性。研究人员设想，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调理。

据介绍，尽管针对可有可无的系抗原（如B细胞急性淋巴细胞白血病中的CD19）观察到了相当大的疗效，但由于缺乏肿瘤限制性抗原，过继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HSPC或分化的髓系细胞表达的基因为靶标，会产生难以承受的靶上/瘤外毒性。

附：英文原文

Title: Epitope editing enables targeted immunotherapy of acute myeloid leukaemia

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

Issue&Volume: 2023-08-30

Abstract: Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3,4,5. 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.

DOI: 10.1038/s41586-023-06496-5

Source: https://www.nature.com/articles/s41586-023-06496-5