Venetoclax Increases Intratumoral Effector T Cells and Antitumor Efficacy in Combination with Immune Checkpoint Blockade.

Abstract

The antiapoptotic protein BCL2 plays critical roles in regulating lymphocyte development and immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL2 is critical for antitumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL2, would influence the antitumor activity of immune checkpoint inhibitors (ICI). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the antitumor efficacy of ICIs accompanied by the increase of PD-1+ T effector memory cells. Venetoclax did not impair human T-cell function in response to antigen stimuli in vitro and did not antagonize T-cell activation induced by anti-PD-1. Furthermore, we demonstrate that the antiapoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy. SIGNIFICANCE: The antiapoptotic oncoprotein BCL2 plays critical roles in tumorigenesis, tumor survival, lymphocyte development, and immune system regulation. Here we demonstrate that venetoclax, the first FDA/European Medicines Agency-approved BCL2 inhibitor, unexpectedly can be combined preclinically with immune checkpoint inhibitors to enhance anticancer immunotherapy, warranting clinical evaluation of these combinations.This article is highlighted in the In This Issue feature, p. 1.

• Authors: Frederick J Kohlhapp, Dipica Haribhai, Rebecca Mathew, Ryan Duggan, Paul A Ellis, Rui Wang, Elisabeth A Lasater, Yan Shi, Nimita Dave, Jacob J Riehm, Valerie A Robinson, An D Do, Yijin Li, Christine J Orr, Deepak Sampath, Aparna Raval, Mark Merchant, Anahita Bhathena, Ahmed Hamed Salem, Keith M Hamel, Joel D Leverson, Cherrie Donawho, William N Pappano, Tamar Uziel
• Journal: Cancer discovery (Cancer Discov) Vol. 11 Issue 1 Pg. 68-79 (01 2021) ISSN: 2159-8290 [Electronic] United States
• PMID: 32887697 (Publication Type: Journal Article)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Immune Checkpoint Inhibitors
• Sulfonamides
• venetoclax

Topics

• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Immune Checkpoint Inhibitors
• Sulfonamides (pharmacology)
• T-Lymphocytes