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

Autor:	Biedermann A; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Patra-Kneuer M; Translational Research, MorphoSys AG, Planegg., Mougiakakos D; Department of Hematology and Oncology, Otto-von-Guericke University (OVGU) Magdeburg, Magdeburg., Büttner-Herold M; Department of Nephropathology, Institute of athology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen., Mangelberger-Eberl D; Translational Research, MorphoSys AG, Planegg., Berges J; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Kellner C; Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich., Altmeyer S; Medizinische Klinik I, Saarland University Medical School, Homburg/Saar., Bittenbring JT; Medizinische Klinik I, Saarland University Medical School, Homburg/Saar., Augsberger C; Translational Research, MorphoSys AG, Planegg., Ilieva-Babinsky K; Translational Research, MorphoSys AG, Planegg., Haskamp S; Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Beier F; Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Medical School, Aachen., Lischer C; Department of Dermatology, University Hospital Erlangen, Erlangen, GER., Vera J; Department of Dermatology, University Hospital Erlangen, Erlangen, GER., Lührmann A; Mikrobiologisches Institut, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen., Bertz S; Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)., Völkl S; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Jacobs B; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Steidl S; Translational Research, MorphoSys AG, Planegg., Mackensen A; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen., Bruns H; Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen. heiko.bruns@uk-erlangen.de.
Jazyk:	angličtina
Zdroj:	Haematologica [Haematologica] 2024 Dec 01; Vol. 109 (12), pp. 3928-3940. Date of Electronic Publication: 2024 Dec 01.
DOI:	10.3324/haematol.2023.284795
Abstrakt:	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.
Databáze:	MEDLINE
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