Chimeric antigen receptor: a cell therapy based approach for the treatment of acute myeloid leukemia

Despite the progress in the treatment of acute myeloid leukemia (AML) achieved in the last decades, a significant number of patients are still refractory to or relapse after standard cures. Hence, to improve cure rates of AML, it is crucial to develop novel therapeutic strategies. Immunotherapy with T cells genetically modified to express chimeric antigen receptors (CARs) represent a valid option in this sense. CARs are artificial molecules constituted by an extracellular-antigen-binding domain derived from a monoclonal antibody and an intracellular-signalling region that is immediately triggered after antigen recognition. Therefore, CARs combine the antigen binding properties of mononoclonal antibodies to T cell mediated effector functions, including the killing mechanism -that might be active against antibody resistant targets-, cytokine secretion- that might boost the anti-tumoral immune response- and capacity to efficiently home and infiltrate tumor sites. Different CARs have been generated so far, against a wide range of surface molecules expressed by many tumors and, currently, several phase I clinical trials are undergoing and the results obtained so far are very encouraging. The CARs approach can be employed to selectively target AML cells due to the overexpression of myeloid antigens, like CD33 and CD123. We recently demonstrated that expression of CD33-specific CARs in a population of ex-vivo activated T cells, called “cytokine induced killer” (CIK) cells, confers them potent in vitro anti-leukemic functions. However, since CD33 antigen is also expressed on normal haematopoietic stem/progenitors cells (HSPCs) resulting in a potential severe impairment of normal myelopoiesis, CD123 has recently been proposed as a new potential attractive molecule based on its differential expression pattern, being widely overexpressed by AML population and at the same time less expressed on HSPCs. In order to improve the safety profile against these cells we develop and tes