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Blood. 2019 May 23;133(21):2291-2304. doi: 10.1182/blood-2018-10-882944. Epub 2019 Feb 22.

Fratricide-resistant CD1a-specific CAR T cells for the treatment of cortical T-cell acute lymphoblastic leukemia.

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Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.
AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain.
Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain.
Haematology Laboratory, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
Institut Catala d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.
Sección de Oncohematología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
Instituto Murciano de Investigación Biosanitaria, Murcia, Spain.
Univerité Paris Diderot and Université Paris-Sud, Unité Mixte de Recherche 967, INSERM, U967, Fontenay-aux-Roses, France.
KU Center for Human Genetics and VIB Center for Cancer Biology, Leuven, Belgium.
Centro de Investigación Biomedica en Red-Oncología, Instituto de Salud Carlos III, Barcelona, Spain; and.
Instituciò Catalana de Recerca i Estudis Avançats, Barcelona, Spain.


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.

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