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

• Published in: Blood Vol. 133; no. 21; pp. 2291 - 2304
• Main Authors: Sánchez-Martínez, Diego, Baroni, Matteo L., Gutierrez-Agüera, Francisco, Roca-Ho, Heleia, Blanch-Lombarte, Oscar, González-García, Sara, Torrebadell, Montserrat, Junca, Jordi, Ramírez-Orellana, Manuel, Velasco-Hernández, Talía, Bueno, Clara, Fuster, José Luís, Prado, Julia G., Calvo, Julien, Uzan, Benjamin, Cools, Jan, Camos, Mireia, Pflumio, Françoise, Toribio, María Luisa, Menéndez, Pablo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2019; American Society of Hematology
• Subjects: Animals; Antigens, CD1 - immunology; Drug Resistance, Neoplasm - immunology; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive; Jurkat Cells; Mice; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - immunology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - therapy; Receptors, Chimeric Antigen - immunology; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2018-10-882944

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. •CD1a CARTs exhibit specific and robust cytotoxicity in vitro and in vivo using both T-ALL cell lines and primary coT-ALL cells.•CD1a CARTs are fratricide resistant and exhibit long-term persistence in vivo with antileukemic activity in rechallenge experiments. [Display omitted]