Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab.

Biedermann A, Patra-Kneuer M, Mougiakakos D, Büttner-Herold M, Mangelberger-Eberl D, Berges J, Kellner C, Altmeyer S, Bittenbring JT, Augsberger C, Ilieva-Babinsky K, Haskamp S, Beier F, Lischer C, Vera J, Lührmann A, Bertz S, Völkl S, Jacobs B, Steidl S, Mackensen A, Bruns H (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Haematologica Ferrata Storti Foundation

Book Volume: 109

Pages Range: 3928-3940

Journal Issue: 12

DOI: 10.3324/haematol.2023.284795

Abstract

Macrophages are one of the key mediators of the therapeutic effects exerted by monoclonal antibodies, such as the anti-CD19 antibody tafasitamab, approved in combination with lenalidomide for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL). However, antibody-dependent cellular phagocytosis (ADCP) in the tumor microenvironment can be counteracted by increased expression of the inhibitory receptor SIRPα on macrophages and its ligand, the immune checkpoint molecule CD47, on tumor cells. The aim of this study was to investigate the impact of the CD47-SIRPα axis on tafasitamab- mediated phagocytosis and explore the potential of anti-CD47 blockade to enhance its antitumor activity. Elevated expression of both SIRPα and CD47 was observed in DLBCL patient-derived lymph node biopsies compared to healthy control lymph nodes. CRISPR-mediated CD47 overexpression affected tafasitamab-mediated ADCP in vitro and increased expression of SIRPα on macrophages correlated with decreased ADCP activity of tafasitamab against DLBCL cell lines. A combination of tafasitamab and an anti-CD47 blocking antibody enhanced ADCP activity of in vitro-generated macrophages. Importantly, tafasitamab-mediated phagocytosis was elevated in combination with CD47 blockade using primary DLBCL cells and patient-derived lymphoma-associated macrophages in an autologous setting. Furthermore, lymphoma cells with low CD19 expression were efficiently eliminated by the combination treatment. Finally, combined treatment of tafasitamab and an anti-CD47 antibody resulted in enhanced tumor volume reduction and survival benefit in lymphoma xenograft mouse models. These findings provide evidence that CD47 blockade can enhance the phagocytic potential of tumor-targeting immunotherapies such as tafasitamab and suggest that there is value in exploring the combination in the clinic.

Authors with CRIS profile

Alexander Biedermann Department of Medicine 5 – Haematology and Oncology Maike Büttner-Herold Department of Nephropathology Johannes Berges Department of Medicine 5 – Haematology and Oncology Stefan Haskamp Lehrstuhl für Humangenetik Christopher Lischer Department of Dermatology Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) Anja Lührmann Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene Simone Bertz Institute of Pathology Simon Völkl Department of Medicine 5 – Haematology and Oncology Benedikt Jacobs Department of Medicine 5 – Haematology and Oncology Andreas Mackensen Lehrstuhl für Innere Medizin V Heiko Bruns Department of Medicine 5 – Haematology and Oncology

Involved external institutions

MorphoSys AG DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Otto-von-Guericke-Universität Magdeburg DE Germany (DE) Universitätsklinikum des Saarlandes (UKS) DE Germany (DE) Klinikum der Universität München DE Germany (DE)

How to cite

APA:

Biedermann, A., Patra-Kneuer, M., Mougiakakos, D., Büttner-Herold, M., Mangelberger-Eberl, D., Berges, J.,... Bruns, H. (2024). Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab. Haematologica, 109(12), 3928-3940. https://doi.org/10.3324/haematol.2023.284795

MLA:

Biedermann, Alexander, et al. "Blockade of the CD47/SIRPα checkpoint axis potentiates the macrophage-mediated antitumor efficacy of tafasitamab." Haematologica 109.12 (2024): 3928-3940.

BibTeX: Download