Kohlhapp et al. evaluated the rationale for the combination of Venetoclax, an FDA-approved BCL-2-specific inhibitor, with immune checkpoint inhibitors using syngeneic tumor models. Venetoclax enhanced the antitumor efficacy of anti-PD-1/PD-L1 inhibitors in a T cell-dependent manner and upregulated intratumoral PD-1+CD8+ T effector memory (TEM) cells. In vitro treatment of human PBMCs with Venetoclax decreased naive T cells, but increased relative proportions of TEM and activated T cells, with increased BCL-XL expression. Venetoclax did not abrogate T cell function in vitro and increased the proportion of effector cells in healthy human subjects.
Contributed by Shishir Pant
ABSTRACT: The anti-apoptotic protein BCL-2 plays critical roles in regulating lymphocyte development, immune responses, and has also been implicated in tumorigenesis and tumor survival. However, it is unknown whether BCL-2 is critical for anti-tumor immune responses. We evaluated whether venetoclax, a selective small-molecule inhibitor of BCL-2, would influence the anti-tumor activity of immune checkpoint inhibitors (ICIs). We demonstrate in mouse syngeneic tumor models that venetoclax can augment the anti-tumor 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. Further, we demonstrate that the anti-apoptotic family member BCL-XL provides a survival advantage in effector T cells following inhibition of BCL-2. Taken together, these data provide evidence that venetoclax should be further explored in combination with ICIs for cancer therapy.
Author Info: (1) Oncology Discovery, AbbVie Inc. (2) Translational Oncology, AbbVie Inc. (3) Oncology Discovery, AbbVie Inc. (4) Oncology Discovery, AbbVie Inc. (5) Oncology Discovery, AbbVie,
Author Info: (1) Oncology Discovery, AbbVie Inc. (2) Translational Oncology, AbbVie Inc. (3) Oncology Discovery, AbbVie Inc. (4) Oncology Discovery, AbbVie Inc. (5) Oncology Discovery, AbbVie, Inc. (6) Oncology Discovery, AbbVie, Inc. (7) Translational Oncology, Genentech, Inc. (8) AbbVie, Inc. (9) James L. Winkle College of Pharmacy, University of Cincinnati. (10) Translational Oncology, AbbVie Inc. (11) Oncology Discovery, AbbVie, Inc. (12) Oncology Biomarker Development, Genentech Inc. (13) Oncology Biomarker Development, Genentech. (14) Translational Oncology, Genentech, Inc. (15) Research, Ultragenyx. (16) Genentech, Inc. (17) Department of Translational Oncology, Genentech. (18) Oncology Discovery, AbbVie, Inc. (19) Clinical Pharmacology and Pharmacometrics, AbbVie Inc. (20) Oncology Discovery, AbbVie Inc. (21) Oncology Development, AbbVie, Inc. (22) Oncology Discovery, AbbVie Inc. (23) Oncology Discovery, AbbVie Inc. (24) Translational Oncology, AbbVie Inc. tamar.uziel@abbvie.com.
