T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia

Abstract

Purpose of review The purpose of this article is to discuss the rationale of targeting CD123 using chimeric antigen receptor (CAR) T cells for the treatment of leukemia. Recent findings CD123 is a leukemia associated antigen that expresses at high levels in leukemic stem cells and leukemic blasts and low level in normal hematopoietic stem / progenitor cells. Immune-based therapies targeting CD123 are being developed. Preclinical data suggest that CD123 CAR T cells exhibit potent anti-leukemic activity and various impacts on normal hematopoiesis. Summary CD123 is an attractive surface target for novel anti-leukemic therapies. CD123 CAR T cell based immunotherapy is a promising treatment for patients with relapsed or refractory acute myeloid leukemia.

Universal monitoring of minimal residual disease in acute myeloid leukemia

“…Another marker recently reported to be associated with leukemia stem cells, CD99 (55), was also overexpressed in AML cells according to both our gene expression analysis and subsequent flow cytometric validation. It is noteworthy that CD99 has been proposed to be a targetable marker for immunotherapy (55), and CD123, another marker overexpressed in our group, is being targeted by antibodies and chimeric antigen receptor-T cells for the treatment of AML (47,56). While our objective was the identification of markers of AML to track MRD, the resulting data warrant further exploration for targetable markers preferentially expressed in AML cells.…”

The promise of chimeric antigen receptor T cells (CARTs) in leukaemia

“…A 123‐CD28 ζ CART at City of Hope, and 123‐4‐1BB ζ CART at PENN, have both demonstrated potent leukaemia killing ability in pre‐clinical models, but have produced inconsistent results with regard to the myeloablative effect on healthy CD123 + cells (Mardiros et al , ; Gill et al , ). An on‐going phase I study at City of Hope (NCT02159495) using lentivirally transduced CD28 ζ CARTs include a truncated EGFR placed in the CART allowing for cetuximab‐induced suicide if required (Mardiros et al , ). Our currently ongoing phase I trial at PENN (NCT 02623582) takes a different approach by using repeated infusions of an mRNA transduced CART which results in only transient CAR expression because there is no permanent genome modification.…”

Cellular Immunotherapy for Hematologic Malignancies: Beyond Bone Marrow Transplantation

“…The CS-1 antigen is another therapeutic option for CAR T cell therapy in light chain amyloidosis [124]. In AML, a number of targets for CAR T cells have been proposed based on preclinical models, including CD123 [125,126], LeY antigen [127], and folate receptor-β [128]. The FDA recently halted the use of an allogeneic CAR T cell product targeting CD123 because of safety concerns, highlighting the importance of regulatory oversight in translating this new technology.…”