FLT3-directed UniCAR T-cell therapy of Acute Myeloid Leukaemia

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform “UniCAR” is currently under early clinical investigation. Recently, first proof-of-concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to a high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off-switch of UniCAR T-cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T-cells for the therapy of AML.