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Atar, D.* ; Ruoff, L.* ; Mast, A.S.* ; Krost, S.* ; Moustafa-Oglou, M.* ; Scheuermann, S.* ; Kristmann, B.* ; Feige, M.J.* ; Canak, A.B.* ; Wolsing, K.* ; Schlager, L.* ; Schilbach, K.* ; Zekri, L.* ; Ebinger, M.* ; Nixdorf, D.* ; Subklewe, M.* ; Schulte, J.H.* ; Lengerke, C.* ; Jeremias, I. ; Werchau, N.* ; Mittelstaet, J.* ; Lang, P.* ; Handgretinger, R.* ; Schlegel, P.G.* ; Seitz, C.M.*

Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia.

Leukemia, DOI: 10.1038/s41375-024-02351-2 (2024)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Targeting AML by chimeric antigen receptor T-cells (CAR-T) is challenging due to the promiscuous expression of AML-associated antigens in healthy hematopoiesis and high degree of inter- and intratumoral heterogeneity. Here, we present single-cell expression data of AML-associated antigens in 30 primary pediatric AML samples. We identified CD33, CD38, CD371, IL1RAP and CD123 as the most frequently expressed. Notably, high variability was observed not only across the different patient samples but also among leukemic cells of the same patient suggesting the necessity of multiplexed targeting approaches. To address this need, we utilized our modular Adapter CAR (AdCAR) platform, enabling precise qualitative and quantitative control over CAR-T-cell function. We show highly efficient and target-specific activity for newly generated adapter molecules (AMs) against CD33, CD38, CD123, CD135 and CD371, both in vitro and in vivo. We reveal that inherent intratumoral heterogeneity in antigen expression translates into antigen escape and therapy failure to monotargeted CAR-T therapy. Further, we demonstrate in PDX models that rational combinatorial targeting by AdCAR-T-cells can cure heterogenic disease. In conclusion, we elucidate the clinical relevance of heterogeneity in antigen expression in pediatric AML and present a novel concept for precision immunotherapy by combinatorial targeting utilizing the AdCAR platform.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Receptor; Immunotherapy; Cancer; Switch; States
Sprache englisch
Veröffentlichungsjahr 2024
HGF-Berichtsjahr 2024
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Zeitschrift Leukemia
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Stem Cell and Neuroscience
PSP-Element(e) G-506600-001
Förderungen Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
DOI 10.1038/s41375-024-02351-2
WOS ID 001282679300001
Scopus ID 85200328978
PubMed ID 39095503
Erfassungsdatum 2024-09-24
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