Cargando…

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

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 l...

Descripción completa

Detalles Bibliográficos
Autores principales: 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, Schewe, Denis M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9631674/
https://www.ncbi.nlm.nih.gov/pubmed/35820018
http://dx.doi.org/10.1182/bloodadvances.2022007364
Descripción
Sumario: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.