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

Diego Sánchez-Martínez, Matteo L. Baroni, Francisco Gutierrez-Agüera, Heleia Roca-Ho, Oscar Blanch-Lombarte, Sara González-García, Montserrat Torrabadell, 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 and Pablo Menéndez

Key points

  • CD1a CARTs show specific and robust cytotoxicity in vitro and antileukemic activity in vivo using both T-ALL cell lines and primary cortical T-ALL cells.

  • CD1a CARTs are fratricide-resistant and show long-term persistence in vivo with antileukemic activity in re-challenge experiments.

Abstract

Relapsed/refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) has a dismal outcome, and no effective targeted immunotherapies for T-ALL exist. The extension of chimeric antigen receptor T-cells (CARTs) to T-ALL remains challenging because the shared expression of target antigens between CARTs and T-ALL blasts leads to CARTs fratricide. CD1a is exclusively expressed in cortical T-ALLs (coT-ALL), a major subset of T-ALL, and retained at relapse. Here, we report 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 pre-clinically 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 supports the therapeutic and safe use of fratricide-resistant CD1a-CARTs for R/R coT-ALL.

  • Submitted October 29, 2018.
  • Accepted February 18, 2019.