Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis

Vogiatzi, Fotini; Heymann, Julia; Müller, Kristina; Winterberg, Dorothee; Drakul, Aneta; Rösner, Thies; Lenk, Lennart; Heib, Michelle; Gehlert, Carina Lynn; Cario, Gunnar; Schrappe, Martin; Claviez, Alexander; Bornhauser, Beat; Bourquin, Jean-Pierre; Bomken, Simon; Adam, Dieter; Frielitz, Fabian-Simon; Maecker-Kolhoff, Britta; Stanulla, Martin; Valerius, Thomas; Peipp, Matthias; Kellner, Christian und Schewe, Denis M. (2022): Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis. In: Blood Advances, Bd. 6, Nr. 16: S. 4847-4858

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2473-9529
• Sprache: Englisch