Título:
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41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
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Autor/a:
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Libero Baroni, Matteo; Sánchez Martínez, Diego; Gutiérrez-Agüera, Francisco; Roca Ho, Heleia; Castellà, Maria; Zanetti, S. R.; Velasco-Hernández, Talia; Díaz de la Guardia, Rafael; Castaño Cardoso, Julio; Anguita, Eduardo; Vives Polo, Susana; Nomdedeu, Josep; Lapillone, H.; Bras, A. E.; van der Velden, V. H. J.; Junca, Jordi; Marin, P.; Bataller, Alex; Esteve Reyner, Jordi; Vick, B.; Jeremias, I.; Lopez, A.; Sorigue, Marc; Bueno, Clara; Menéndez Bujan, Pablo; Universitat Autònoma de Barcelona
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Abstract:
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Altres ajuts: We thank CERCA/Generalitat de Catalunya and Fundació Josep Carreras-Obra Social la Caixa for their institutional support. PM acknowledges financial support from theSpanish Cancer Research Association (AECC-Semilla19), the Fundación Uno entre Cienmil, the Obra Social La Caixa (LCF/PR/HR19/52160011), the Leo Messi Foundation, the Banco Santander Foundation and the "Heroes hasta la médula" initiative. |
Abstract:
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BACKGROUND: Acute 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. METHODS: We 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. RESULTS: Here, 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. CONCLUSIONS: This 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. |
Materia(s):
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-T lymphocytes -Cell engineering -Immunotherapy, adoptive |
Derechos:
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open access
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Article |
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Uri:
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https://ddd.uab.cat/record/236433
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