@article{9433a03b578549629a988400274a5165,
title = "Venetoclax enhances T cell–mediated antileukemic activity by increasing ROS production",
abstract = "Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent azacytidine, achieves complete remission with or without count recovery in ∼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.",
author = "Lee, {Jong Bok} and Khan, {Dilshad H.} and Rose Hurren and Mingjing Xu and Yoosu Na and Hyeonjeong Kang and Sara Mirali and Xiaoming Wang and Marcela Gronda and Yulia Jitkova and Neil MacLean and Andrea Arruda and Zoe Alaniz and Konopleva, {Marina Y.} and Michael Andreeff and Minden, {Mark D.} and Li Zhang and Schimmer, {Aaron D.}",
note = "Funding Information: The authors thank all the donors and patients who participated in this study. They also thank Jill Flewelling (Princess Margaret Cancer Centre) for administrative assistance and the Leukemia Tissue Bank (Princess Margaret Cancer Centre) for providing the primary AML samples, and IsoPlexis for assistance in generating the single-cell cytokine data. This work was supported by Canadian Cancer Society Impact Grant 704121, Canadian Institutes of Health Research Grant 419699, and Maria H. Bacardi Chair in Transplantation (all to L.Z.); the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario (all to A.D.S.); and the National Institutes of Health, National Cancer Institute (P30 CA16672), Cancer Prevention & Research Institute of Texas (CPRIT) RP160693, and Haas Chair in Genetics (all to M.A.). Funding Information: This work was supported by Canadian Cancer Society Impact Grant 704121, Canadian Institutes of Health Research Grant 419699, and Maria H. Bacardi Chair in Transplantation (all to L.Z.); the Ontario Institute for Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario (all to A.D.S.); and the National Institutes of Health, National Cancer Institute (P30 CA16672), Cancer Prevention & Research Institute of Texas (CPRIT) RP160693, and Haas Chair in Genetics (all to M.A.). Funding Information: Conflict-of-interest disclosure: A.D.S. has received research funding from Takeda Pharmaceuticals and Medivir AB; has consulting fees/honorarium from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals; and holds stock in AbbVie. M.D.M. is a consultant for Astellas, AbbVie, and Celgene. L.Z. received funding and consulting fee/honorarium from WYZE Biotech Co Ltd; and holds stock in AbbVie. A.D.S., J.B.L., and L.Z. are inventors on patent applications claiming the use of DNTs for the treatment of AML. J.B.L. and L.Z. are cofounders of Denote Therapeutics. The remaining authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",
year = "2021",
month = jul,
day = "22",
doi = "10.1182/blood.2020009081",
language = "English (US)",
volume = "138",
pages = "234--245",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "3",
}