12.30.21

Anti-CD123 CAR T Cell Cytotoxicity Against AML

El Khawanky N, Hughes A, Yu W, et al. Demethylating Therapy Increases Anti-CD123 CAR T Cell Cytotoxicity Against Acute Myeloid Leukemia. Nature Communications. 2021; (doi: 10.1038/s41467-021-26683-0).

Chimeric antigen receptor T-cell (CAR-T) treatment produces less than optimal outcomes in acute myeloid leukemia (AML), but researchers have found that 5'-azacitidine (AZA) enhances the effect of immunotherapy in this setting. While toxicity on healthy hematopoietic progenitor cells and low CAR T cell persistence due to loss of target antigen are part of the frustration with CAR-T for AML, the team developed an anti-CD123 CAR that displayed anti-AML behavior without compromising the normal hematopoietic system or damaging epithelial tissue. These third-generation CAR T cells inhibited leukemic activity in mice, but not enough to eradicate the disease. To increase efficacy, investigators pre-treated AML cells or leukemia-bearing mice with AZA, a DNA methyltransferase inhibitor that increases expression of CD123 on cancer cells. In the mice, which received an infusion of anti-CD123 CAR-T cells following pre-treatment with AZA, AML rejection in vivo increased, as did survival rates. AML cells, meanwhile, generated more CTLA-4negative CAR T-cells when pretreated with AZA than when treated with CAR-T only; and those CTLA-4negative CAR T cells expressed more robust cytotoxicity against leukemia cells in vitro and in vivo than did CTLA-4positive CAR-T cells. The findings support future clinical research coupling AZA and anti-CD123 CAR-T therapy as an intervention against AML.

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