Buchumschlag

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

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 applic...

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Hauptverfasser: Müller, Kristina (Verfasst von) , Vogiatzi, Fotini (Verfasst von) , Winterberg, Dorothee (Verfasst von) , Rösner, Thies (Verfasst von) , Lenk, Lennart (Verfasst von) , Bastian, Lorenz (Verfasst von) , Gehlert, Carina L. (Verfasst von) , Autenrieb, Marie-Pauline (Verfasst von) , Brüggemann, Monika (Verfasst von) , Cario, Gunnar (Verfasst von) , Schrappe, Martin (Verfasst von) , Kulozik, Andreas (Verfasst von) , Eckert, Cornelia (Verfasst von) , Bergmann, Anke Katharina (Verfasst von) , Bornhauser, Beat (Verfasst von) , Bourquin, Jean-Pierre (Verfasst von) , Valerius, Thomas (Verfasst von) , Peipp, Matthias (Verfasst von) , Kellner, Christian (Verfasst von) , Schewe, Denis Martin (Verfasst von)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 7 July 2022
In: Blood
Year: 2022, Jahrgang: 140, Heft: 1, Pages: 45-57
ISSN:1528-0020
DOI:10.1182/blood.2021014485
Online-Zugang:Resolving-System, lizenzpflichtig: http://dx.doi.org/10.1182/blood.2021014485
Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/blood.2021014485
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 25.09.2022
Beschreibung:Online Resource
ISSN:1528-0020
DOI:10.1182/blood.2021014485

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