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

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.