Allogeneic TCRαβ deficient CAR T-cells targeting CD123 in acute myeloid leukemia

Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCR alpha beta neg T cells generated from healthy donors using TALEN (R) gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML. CD123, the interleukin-3 receptor alpha chain, is aberrantly expressed in acute myeloid leukemia blasts and leukemia stem cells. Here the authors report the design and characterize the anti-tumor activity of allogeneic CD123-targeted CAR-T cells as a therapeutic approach for acute myeloid leukemia.