Venetoclax enhances T cell-mediated anti-leukemic activity by increasing ROS production

Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve elderly patients unfit for conventional intensive chemotherapy. However, the mechanism of action of this drug c...

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Bibliographic Details
Published in:Blood 2021-03
Main Authors: Lee, JongBok, Khan, Dilshad H, Hurren, Rose, Xu, Mingjing, Na, Yoosu, Kang, Hyeonjeong, Mirali, Sara, Wang, Xiaoming, Gronda, Marcela Victoria, Jitkova, Yulia, MacLean, Neil, Arruda, Andrea, Alaniz, Zoe, Konopleva, Marina Y, Andreeff, Michael, Minden, Mark D, Zhang, Li, Schimmer, Aaron D
Format: Article
Language:English
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Summary:Venetoclax, a Bcl-2 inhibitor, in combination with the hypomethylating agent, Azacytidine, achieves complete response with or without count recovery in approximately 70% of treatment-naïve 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 AML in vitro and in vivo. Venetoclax enhanced T cell effector function by increasing ROS 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 ROS generation and activated T cells. Collectively, this study demonstrates 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.
ISSN:1528-0020