41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo
Libero Baroni, Matteo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Sánchez Martínez, Diego (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Gutiérrez-Agüera, Francisco (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Roca Ho, Heleia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Castellà, Maria (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Zanetti, S. R (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Velasco-Hernández, Talia (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Díaz de la Guardia, Rafael (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Castaño Cardoso, Julio (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Anguita, Eduardo (Hospital Clínico San Carlos (Madrid))
Vives Polo, Susana (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Nomdedeu, Josep (Institut d'Investigació Biomèdica Sant Pau)
Lapillone, Helene (Centre de Recherce Saint-Antoine. Armand-Trousseau Childrens Hospital. Île-de-France)
Bras, Anne E. (Immunology Department. Erasmus Medical Center)
van der Velden, Vincent H. J. (Immunology Department. Erasmus Medical Center)
Junca, Jordi (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Marin, Pedro (Hospital Clínic i Provincial de Barcelona)
Bataller, Alex (Hospital Clínic i Provincial de Barcelona)
Esteve Reyner, Jordi (Hospital Clínic i Provincial de Barcelona)
Vick, Binje (Helmholtz Center. Munich German Research Center for Environmental Health)
Jeremias, Irmela (Pediatrics Department. Munich University Hospital Dr von Hauner Children's Hospital. Munchen)
Lopez, Angel (Human Immunology Department. Centre for Cancer Biology)
Sorigue, Marc (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Bueno, Clara (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Menéndez Bujan, Pablo (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	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.
Ayudas:	Ministerio de Economía y Competitividad SAF2016-80481-R Instituto de Salud Carlos III PI17-01028
Nota:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	T lymphocytes ; Cell engineering ; Immunotherapy, adoptive
Publicado en:	Journal for immunotherapy of cancer, Vol. 8 Núm. 1 (january 2020) , ISSN 2051-1426

DOI: 10.1136/jitc-2020-000845
PMID: 32527933

12 p, 2.0 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Instituto de Investigación contra la Leucemia Josep Carreras
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Institut de Recerca Sant Pau
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