Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland.
Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Zurich, Switzerland.
Exp Hematol. 2021 Mar;95:31-45. doi: 10.1016/j.exphem.2021.01.003. Epub 2021 Jan 20.
Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.
精确替换病变或功能失调的器官是再生医学的目标，长期以来，这一目标似乎遥不可及。在造血干细胞移植领域，随着基因编辑技术和新型调理剂进入临床领域，这一目标正在成为现实。靶向性免疫耗竭造血干细胞（HSCs），这种干细胞处于造血系统的最根本位置，将使血液系统疾病患者能够进行更具选择性和潜在更有效的造血干细胞移植。与基于电离辐射和化疗的现有调理方案不同，免疫调理将保留成熟的造血细胞，并引起更少的炎症和对其他器官的非特异性附带损伤。针对干细胞抗原 CD117 的生物制剂是实现这一目标的领跑者，并且在健康 HSCs 的耗竭方面显示出了临床前活性。抗 CD117 抗体作为调理剂的价值目前正在早期临床试验中进行评估。虽然对于不需要完全替换病变细胞的良性血液系统疾病，轻度、基于抗体的免疫调理概念可能是合适的，但对于治疗和消除血液干细胞恶性肿瘤（如急性髓细胞白血病和骨髓增生异常综合征），则需要更高的疗效。与裸抗体相比，抗体-药物偶联物、双特异性 T 细胞结合和激活抗体（TEAs）或嵌合抗原受体（CAR）T 细胞可能提供更高的疗效，而且与目前的遗传毒性调理方法相比，具有更高的耐受性和安全性。在这里，我们总结了用于治疗 HSC 疾病的免疫调理概念的现状，并概述了潜在的未来发展方向。
