Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL

• Verfasst von: Müller, Kristina [VerfasserIn]
• Verfasst von: Vogiatzi, Fotini [VerfasserIn]
• Verfasst von: Winterberg, Dorothee [VerfasserIn]
• Verfasst von: Rösner, Thies [VerfasserIn]
• Verfasst von: Lenk, Lennart [VerfasserIn]
• Verfasst von: Bastian, Lorenz [VerfasserIn]
• Verfasst von: Gehlert, Carina L. [VerfasserIn]
• Verfasst von: Autenrieb, Marie-Pauline [VerfasserIn]
• Verfasst von: Brüggemann, Monika [VerfasserIn]
• Verfasst von: Cario, Gunnar [VerfasserIn]
• Verfasst von: Schrappe, Martin [VerfasserIn]
• Verfasst von: Kulozik, Andreas [VerfasserIn]
• Verfasst von: Eckert, Cornelia [VerfasserIn]
• Verfasst von: Bergmann, Anke K. [VerfasserIn]
• Verfasst von: Bornhauser, Beat [VerfasserIn]
• Verfasst von: Bourquin, Jean-Pierre [VerfasserIn]
• Verfasst von: Valerius, Thomas [VerfasserIn]
• Verfasst von: Peipp, Matthias [VerfasserIn]
• Verfasst von: Kellner, Christian [VerfasserIn]
• Verfasst von: Schewe, Denis Martin [VerfasserIn]
• Titel: Combining daratumumab with CD47 blockade prolongs survival in preclinical models of pediatric T-ALL
• Verf.angabe: Kristina Müller, Fotini Vogiatzi, Dorothee Winterberg, Thies Rösner, Lennart Lenk, Lorenz Bastian, Carina L. Gehlert, Marie-Pauline Autenrieb, Monika Brüggemann, Gunnar Cario, Martin Schrappe, Andreas E. Kulozik, Cornelia Eckert, Anke K. Bergmann, Beat Bornhauser, Jean-Pierre Bourquin, Thomas Valerius, Matthias Peipp, Christian Kellner, and Denis M. Schewe
• E-Jahr: 2022
• Jahr: 7 July 2022
• Umfang: 13 S.
• Fussnoten: Gesehen am 25.09.2022
• Titel Quelle: Enthalten in: Blood
• Ort Quelle: Washington, DC : American Society of Hematology, 1946
• Jahr Quelle: 2022
• Band/Heft Quelle: 140(2022), 1, Seite 45-57
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood.2021014485
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1811021840

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignant disease affecting children. Although therapeutic strategies have improved, T-cell acute lymphoblastic leukemia (T-ALL) relapse is associated with chemoresistance and a poor prognosis. One strategy to overcome this obstacle is the application of monoclonal antibodies. Here, we show that leukemic cells from patients with T-ALL express surface CD38 and CD47, both attractive targets for antibody therapy. We therefore investigated the commercially available CD38 antibody daratumumab (Dara) in combination with a proprietary modified CD47 antibody (Hu5F9-IgG2σ) in vitro and in vivo. Compared with single treatments, this combination significantly increased in vitro antibody-dependent cellular phagocytosis in T-ALL cell lines as well as in random de novo and relapsed/refractory T-ALL patient-derived xenograft (PDX) samples. Similarly, enhanced antibody-dependent cellular phagocytosis was observed when combining Dara with pharmacologic inhibition of CD47 interactions using a glutaminyl cyclase inhibitor. Phase 2-like preclinical in vivo trials using T-ALL PDX samples in experimental minimal residual disease-like (MRD-like) and overt leukemia models revealed a high antileukemic efficacy of CD47 blockade alone. However, T-ALL xenograft mice subjected to chemotherapy first (postchemotherapy MRD) and subsequently cotreated with Dara and Hu5F9-IgG2σ displayed significantly reduced bone marrow infiltration compared with single treatments. In relapsed and highly refractory T-ALL PDX combined treatment with Dara and Hu5F9-IgG2σ was required to substantially prolong survival compared with single treatments. These findings suggest that combining CD47 blockade with Dara is a promising therapy for T-ALL, especially for relapsed/refractory disease harboring a dismal prognosis in patients.