CD123-targeting immunotherapeutic approaches in acute myeloid leukaemia

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.