CD123 CAR T cells for the treatment of myelodysplastic syndrome.

• Autologous T cells derived from MDS patients can be successfully transduced and are highly active in multiple functional assays. • A xenograft model was developed in which high-risk MDS specimens engraft to high levels and thus provide an in vivo model for characterization of MDS stem cell behavior. • Autologous T cells are highly active in our xenograft model and selectively target the CD123-positive population. Importantly, CD123 CAR T cells did not exhibit appreciable targeting of normal hematopoietic stem and progenitor cells. Myelodysplastic syndrome (MDS) is a group of heterogeneous disorders caused by ineffective hematopoiesis and characterized by bone marrow dysplasia and cytopenia. Current treatment options for MDS are limited to supportive care, hypomethylating agents, and stem cell transplant. Most patients eventually succumb to the disease or progress to leukemia. Previously, we found that CD123 can be used to delineate MDS stem cells in patients at high risk for MDS and that the CD123-positive population is biologically distinct from normal hematopoietic stem cells. Furthermore, selective targeting of MDS stem cells can dramatically reduce tumor burden in preclinical models. On the basis of these findings, we propose CD123 as a candidate target for chimeric antigen receptor (CAR) T-cell therapy in high-risk MDS patients. To test this concept, we employed a CAR lentiviral vector containing a CD123-specific single-chain variable fragment in combination with the CD28 costimulatory domain, CD3ζ signaling domain, and truncated estimated glomerular filtration rate. Utilizing this system, we illustrate that CD123 CAR can be expressed on both healthy donor and MDS patient-derived T lymphocytes with high efficiency, leading to the successful elimination of MDS stem cells both in vitro and in patient-derived xenografts. These results provide the concept for the use of CD123-targeted CAR T cells as a therapeutic option for patients with MDS. [ABSTRACT FROM AUTHOR]