Shi Mingyue, Su Ruijun J, Parmar Kamal-Preet, Chaudhry Rahman, Sun Kai, Rao Jianyu, Chen Mingyi
Department of Pathology and Laboratory Medicine, UT Southwestern Medical Center, Dallas, TX 75390, United States.
Department of Hematology, Henan Provincial People's Hospital & Zhengzhou University People's Hospital, Henan, China.
Cardiovasc Hematol Disord Drug Targets. 2019;19(3):195-204. doi: 10.2174/1871529X19666190627100613.
Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.
白血病是一组源自骨髓干细胞的进行性血液系统恶性肿瘤，导致大量癌症死亡。即使采用传统化疗、靶向治疗和异基因干细胞移植（allo-HSCT）等治疗方法，许多患者仍会出现复发/难治性疾病，总体生存率不容乐观。白血病干细胞（LSCs）由基因突变诱导，经历异常且调控不良的增殖过程，这与白血病的演变、复发和耐药性有关。新兴研究表明，白细胞介素3受体α（IL-3Rα）即CD123在LSCs中高度表达，而在正常造血干细胞（HSCs）中不表达，并且与治疗反应、微小残留病（MRD）检测及预后相关。此外，CD123是难治性或复发性白血病LSCs识别和靶向治疗的重要标志物。临床前研究和临床试验中的抗CD123靶向治疗证实了抗CD123中和抗体药物、CD3×CD123双特异性抗体、双亲和重定向（DART）以及正在进行的抗CD123嵌合抗原受体修饰T细胞（CAR-T）疗法的效用。本综述总结了CD123生物学研究及新型CD123靶向治疗开发的最新进展。
