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  • Title: Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.
    Author: El Khawanky N, Hughes A, Yu W, Myburgh R, Matschulla T, Taromi S, Aumann K, Clarson J, Vinnakota JM, Shoumariyeh K, Miething C, Lopez AF, Brown MP, Duyster J, Hein L, Manz MG, Hughes TP, White DL, Yong ASM, Zeiser R.
    Journal: Nat Commun; 2021 Nov 08; 12(1):6436. PubMed ID: 34750374.
    Abstract:
    Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4negative anti-CD123 CAR T cells.
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