Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia

Nadia El Khawanky, Amy Hughes, Wenbo Yu, Renier Myburgh, Tony Matschulla, Sanaz Taromi, Konrad Aumann, Jade Clarson, Janaki Manoja Vinnakota, Khalid Shoumariyeh, Cornelius Miething, Angel F. Lopez, Michael P. Brown, Justus Duyster, Lutz Hein, Markus G. Manz, Timothy P. Hughes, Deborah L. White, Agnes S. M. Yong () and Robert Zeiser ()
Additional contact information
Nadia El Khawanky: South Australian Health and Medical Research Institute (SAHMRI)
Amy Hughes: University of Adelaide
Wenbo Yu: SA Pathology and University of South Australia
Renier Myburgh: University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ)
Tony Matschulla: University of Freiburg
Sanaz Taromi: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Konrad Aumann: University Medical Center Freiburg
Jade Clarson: South Australian Health and Medical Research Institute (SAHMRI)
Janaki Manoja Vinnakota: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Khalid Shoumariyeh: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Cornelius Miething: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Angel F. Lopez: University of Adelaide
Michael P. Brown: University of Adelaide
Justus Duyster: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
Lutz Hein: University of Freiburg
Markus G. Manz: University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ)
Timothy P. Hughes: South Australian Health and Medical Research Institute (SAHMRI)
Deborah L. White: South Australian Health and Medical Research Institute (SAHMRI)
Agnes S. M. Yong: South Australian Health and Medical Research Institute (SAHMRI)
Robert Zeiser: Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg

Nature Communications, 2021, vol. 12, issue 1, 1-20

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26683-0

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