Journal
BLOOD ADVANCES
Volume 6, Issue 16, Pages 4847-4858Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2022007364
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Funding
- Medical Faculty of the Christian-Albrechts University Kiel - Wilhelm Sander Stiftung [2016.110.1]
- Wilhelm Sander Stiftung [2016.110.1]
- Deutsche Jose-Carreras Leukamiestiftung [2016.110.1]
- Deutsche Krebshilfe [DJCLS 17 R/2017, 70113524]
- [70113533]
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The addition of the Bcl-2 inhibitor venetoclax enhances the efficacy of therapeutic antibodies by increasing antibody-dependent cellular phagocytosis mediated by macrophages.
Immunotherapy has evolved as a powerful tool for the treatment of B-cell malignancies, and patient outcomes have improved by combining therapeutic antibodies with conventional chemotherapy. Overexpression of antiapoptotic B-cell lymphoma 2 (Bcl-2) is associated with a poor prognosis, and increased levels have been described in patients with double-hit diffuse large B-cell lymphoma, a subgroup of Burkitt's lymphoma, and patients with pediatric acute lymphoblastic leukemia harboring a t(17;19) translocation. Here, we show that the addition of venetoclax (VEN), a specific Bcl-2 inhibitor, potently enhanced the efficacy of the therapeutic anti-CD20 antibody rituximab, anti-CD38 daratumumab, and anti-CD19-DE, a proprietary version of tafasitamab. This was because of an increase in antibody-dependent cellular phagocytosis by macrophages as shown in vitro and in vivo in cell lines and patient-derived xenograft models. Mechanistically, double-hit lymphoma cells subjected to VEN triggered phagocytosis in an apoptosis-independent manner. Our study identifies the combination of VEN and therapeutic antibodies as a promising novel strategy for the treatment of B-cell malignancies.
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