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

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

Data de publicació online: 23/05/2019 Revista: Immunobiology and Immunotherapy

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.

Autors: Diego Sánchez-Martínez, Matteo L. Baroni, Francisco Gutierrez-Agüera, Heleia Roca-Ho, Oscar Blanch-Lombarte, Sara González-García, Montserrat Torrebadell, Jordi Junca, Manuel Ramírez-Orellana, Talía Velasco-Hernández, Clara Bueno, José Luís Fuster, Julia G. Prado, Julien Calvo, Benjamin Uzan, Jan Cools, Mireia Camos, Françoise Pflumio, María Luisa Toribio, Pablo Menéndez

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