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
  • 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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