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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.

Author information

1
Josep Carreras Leukemia Research Institute, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain.
2
AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain.
3
Centro de Biología Molecular Severo Ochoa CSIC-UAM, Madrid, Spain.
4
Haematology Laboratory, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain.
5
Centro de Investigación Biomédica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain.
6
Institut Catala d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
7
Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.
8
Sección de Oncohematología Pediátrica, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
9
Instituto Murciano de Investigación Biosanitaria, Murcia, Spain.
10
Univerité Paris Diderot and Université Paris-Sud, Unité Mixte de Recherche 967, INSERM, U967, Fontenay-aux-Roses, France.
11
KU Center for Human Genetics and VIB Center for Cancer Biology, Leuven, Belgium.
12
Centro de Investigación Biomedica en Red-Oncología, Instituto de Salud Carlos III, Barcelona, Spain; and.
13
Instituciò Catalana de Recerca i Estudis Avançats, Barcelona, Spain.

Abstract

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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