Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia.
Por:
Sánchez-Martínez D, Baroni ML, Gutierrez-Agüera F, Roca-Ho H, Blanch-Lombarte O, González-García S, Torrebadell-Burriel M, Junca J, Ramírez-Orellana M, Velasco-Hernández T, Bueno C, Fuster JL, Prado JG, Calvo J, Uzan B, Cools J, Camós-Guijosa M, Pflumio F, Toribio ML and Menéndez P
Publicada:
23 may 2019
Ahead of Print:
22 feb 2019
Resumen:
Relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor (CAR) T cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CART fratricide. CD1a is exclusively expressed in cortical T-ALL (coT-ALL), a major subset of T-ALL, and retained at relapse. This article reports that the expression of CD1a is mainly restricted to developing cortical thymocytes, and neither CD34(+) progenitors nor T cells express CD1a during ontogeny, confining the risk of on-target/off-tumor toxicity. We thus developed and preclinically validated a CD1a-specific CAR with robust and specific cytotoxicity in vitro and antileukemic activity in vivo in xenograft models of coT-ALL, using both cell lines and coT-ALL patient-derived primary blasts. CD1a-CARTs are fratricide resistant, persist long term in vivo (retaining antileukemic activity in re-challenge experiments), and respond to viral antigens. Our data support the therapeutic and safe use of fratricide-resistant CD1a-CARTs for relapsed/refractory coT-ALL.
Filiaciones:
Sánchez-Martínez D:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
dsanchez
Baroni ML:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Gutierrez-Agüera F:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Roca-Ho H:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Blanch-Lombarte O:
AIDS Research Institute IrsiCaixa, Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol, Univ. Autonoma de Barcelona, Barcelona, Spain
González-García S:
Centro de Biologia Molecular Severo Ochoa CSIC-UAM, Madrid, Spain
Torrebadell-Burriel M:
Haematology Laboratory, Institut de Recerca Hospital Sant Joan de Deu, Barcelona, Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
Junca J:
ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autonoma de Barcelona, Badalona, Spain
Ramírez-Orellana M:
Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Nino Jesus, Universidad Autonoma de Madrid, Madrid, Spain
Velasco-Hernández T:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Bueno C:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Fuster JL:
Seccion de Oncohematologia Pediatrica, Hospital Clinico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigacion Biosanitaria (IMIB), Murcia, Spain
Prado JG:
AIDS Research Institute IrsiCaixa, Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol, Univ. Autonoma de Barcelona, Barcelona, Spain
Calvo J:
Univerite Paris Diderot and Universite Paris-Sud, UMR 967, INSERM, U967, Fontenay-aux-Roses, France
Uzan B:
Univerite Paris Diderot and Universite Paris-Sud, UMR 967, INSERM, U967, Fontenay-aux-Roses, France
Cools J:
KU Center for Human Genetics and VIB Center for Cancer Biology, Leuven, Belgium
Camós-Guijosa M:
Haematology Laboratory, Institut de Recerca Hospital Sant Joan de Deu, Barcelona, Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain
Pflumio F:
Univerite Paris Diderot and Universite Paris-Sud, UMR 967, INSERM, U967, Fontenay-aux-Roses, France
Toribio ML:
Centro de Biologia Molecular Severo Ochoa CSIC-UAM, Madrid, Spain
Menéndez P:
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
Open Access
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