Journal
BLOOD
Volume 138, Issue 3, Pages 234-245Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020009081
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Funding
- Canadian Cancer Society Impact Grant [704121]
- Canadian Institutes of Health Research Grant [419699]
- Maria H. Bacardi Chair in Transplantation
- Ontario Institute for Cancer Research
- Ontario Ministry of Research and Innovation
- Princess Margaret Cancer Centre Foundation
- Ministry of Long Term Health and Planning in the Province of Ontario
- National Institutes of Health, National Cancer Institute [P30 CA16672]
- Cancer Prevention & Research Institute of Texas (CPRIT) [RP160693]
- Haas Chair in Genetics
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The combination therapy of Venetoclax and azacytidine directly activates T cells, increases reactive oxygen species generation, and enhances cytotoxicity against AML cells. Azacytidine also activates the STING/cGAS pathway, rendering AML cells more susceptible to T cell-mediated cytotoxicity.
Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in similar to 70% of treatment-naive elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug combination is not fully understood. We discovered that venetoclax directly activated T cells to increase their cytotoxicity against acute myeloid leukemia (AML) in vitro and in vivo. Venetoclax enhanced T-cell effector function by increasing reactive oxygen species generation through inhibition of respiratory chain supercomplexes formation. In addition, azacytidine induced a viral mimicry response in AML cells by activating the STING/cGAS pathway, thereby rendering the AML cells more susceptible to T cell-mediated cytotoxicity. Similar findings were seen in patients treated with venetoclax, as this treatment increased reactive oxygen species generation and activated T cells. Collectively, this study presents a new immune-mediated mechanism of action for venetoclax and azacytidine in the treatment of AML and highlights a potential combination of venetoclax and adoptive cell therapy for patients with AML.
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