RT Journal Article
T1 41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
A1 Libero Baroni, Matteo
A1 Anguita Mandly, Eduardo Luis
A1 Menéndez, Pablo
AB BackgroundAcute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.MethodsWe set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.ResultsHere, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.ConclusionsThis study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
PB BMJ Publishing Group Ltd.
SN 2051-1426
YR 2020
FD 2020-06-10
LK https://hdl.handle.net/20.500.14352/117554
UL https://hdl.handle.net/20.500.14352/117554
LA eng
NO Baroni ML, Sanchez Martinez D, Gutierrez Aguera F, et al41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivoJournal for ImmunoTherapy of Cancer 2020;8:e000845. doi: 10.1136/jitc-2020-000845
NO CERCA/Generalitat de Catalunya
NO Fundació Josep Carreras‐Obra Social la Caixa
DS Docta Complutense
RD 17 abr 2025