Department of Biomedicine, Basel University Hospital and University of Basel, Basel, Switzerland.
Transplantation Immunology and Nephrology, Basel University Hospital, Basel, Switzerland.
J Exp Med. 2023 Dec 4;220(12). doi: 10.1084/jem.20231235. Epub 2023 Sep 29.
Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).
使用单克隆抗体 (mAb)、抗体药物偶联物 (ADC)、T 细胞衔接器 (TCE) 或嵌合抗原受体 (CAR) 细胞靶向消除转化或其他失调的细胞对于血液系统疾病非常有效。与 B 细胞恶性肿瘤取得的突破性进展不同，迫切需要为髓系恶性肿瘤找到合适的抗原。白细胞介素 3 (IL-3) 受体 α 链 CD123 在各种血液系统恶性肿瘤中高度表达，包括急性髓系白血病 (AML)。然而，健康造血干细胞和祖细胞 (HSPC) 上共同表达的 CD123 存在着骨髓毒性的风险。我们证明，表位工程化的 HSPC 受到 CD123 靶向免疫疗法的保护而保持功能，但 CD123 缺陷的 HSPC 则表现出竞争劣势。基因组编辑 HSPC 的移植可以实现肿瘤选择性靶向免疫治疗，同时重建一个完全功能性的造血系统。我们设想这种方法广泛适用于其他靶点和细胞，可以使以前无法治疗的靶点能够接受免疫治疗，并允许在移植后继续进行治疗，例如治疗微小残留疾病 (MRD)。
