CD123‐targeting immunotherapeutic approaches in acute myeloid leukaemia

Summary Treatment of relapsed or refractory acute myeloid leukaemia (AML) has remained a significant challenge, with limited available targeted immunotherapies. CD123, or the interleukin‐3 (IL‐3) receptor, has long been known as a potential target expressed on AML blasts, and a range of different approaches to targeting CD123 have been trialled with variable anti‐tumour responses and toxicities observed. Here, we review the clinical outcomes of these therapies, including monoclonal antibodies and antibody‐drug conjugates, as well as bispecific T‐cell engager molecules and chimeric antigen receptor (CAR) T cells. We discuss the potential reasons for therapy‐associated toxicity and limited efficacy, including differential antigen expression, the AML microenvironment and patient‐derived T‐cell fitness. To address these challenges, we highlight novel approaches to CD123 targeting currently in preclinical development. Promising new strategies include combination therapies that target CD123 and other known AML‐associated antigens such as CD33 or CLL‐1, NK‐cell‐based cell therapies, and bispecific‐secreting T cells.