2. Academic Validation
  3. Venetoclax enhances the efficacy of therapeutic antibodies in B-cell malignancies by augmenting tumor cell phagocytosis

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

  • Blood Adv. 2022 Aug 23;6(16):4847-4858. doi: 10.1182/bloodadvances.2022007364.
Fotini Vogiatzi 1,  Julia Heymann 1,  Kristina Müller 1,  Dorothee Winterberg 1,  Aneta Drakul 2,  Thies Rösner 3,  Lennart Lenk 1,  Michelle Heib 4,  Carina Lynn Gehlert 5,  Gunnar Cario 1,  Martin Schrappe 1,  Alexander Claviez 1,  Beat Bornhauser 2,  Jean-Pierre Bourquin 2,  Simon Bomken 6,  Dieter Adam 4,  Fabian-Simon Frielitz 7,  Britta Maecker-Kolhoff 8,  Martin Stanulla 8,  Thomas Valerius 3,  Matthias Peipp 5,  Christian Kellner 9,  Denis M Schewe 10
Affiliations

Affiliations

  • 1 Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 2 Division of Pediatric Oncology, and Children Research Center, University Childreńs Hospital, Zurich, Switzerland.
  • 3 Division of Stem Cell Transplantation and Immunotherapy, Department of Medicine II, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
  • 4 Institute of Immunology, Christian-Albrechts-University Kiel, Kiel, Germany.
  • 5 Department of Medicine II, Division of Antibody-Based Immunotherapy, Christian-Albrechts University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.
  • 6 Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
  • 7 Institute of Social Medicine and Epidemiology, University of Lübeck, Lübeck, Germany.
  • 8 Department of Pediatrics, Hannover Medical School, Hannover, Germany.
  • 9 Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, University Hospital, LMU Munich, Munich, Germany; and.
  • 10 Department of Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
PMID: 35820018 DOI: 10.1182/bloodadvances.2022007364
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.

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