Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis
Fotini Vogiatzi, Julia Heymann, Kristina Müller, Dorothee Winterberg, Aneta Drakul, Thies Rösner, Lennart Lenk, Michelle Heib, Carina Lynn Gehlert, Gunnar Cario, Martin Schrappe, Alexander Claviez, Beat Bornhäuser, Jean‐Pierre Bourquin, Simon Bomken, Dieter Adam, Fabian‐Simon Frielitz, Britta Maecker‐Kolhoff, Martin Stanulla, Thomas Valerius, Matthias Peipp, Christian Kellner, Denis M. Schewe
Abstract
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.