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Zanetti, S.R.* ; Velasco-Hernandez, T.* ; Gutiérrez-Agüera, F.* ; Díaz, V.M.* ; Romecín, P.A.* ; Roca-Ho, H.* ; Sánchez-Martínez, D.* ; Tirado, N.* ; Baroni, M.L.* ; Petazzi, P.* ; Torres-Ruiz, R.A.* ; Molina, O.* ; Bataller, A.* ; Fuster, J.L.* ; Ballerini, P.* ; Juan, M.* ; Jeremias, I. ; Bueno, C.* ; Menéndez, P.*

A novel and efficient tandem CD19- and CD22-directed CAR for B-cell ALL.

Mol. Ther. 30, 550-563 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
CD19-directed chimeric antigen receptor (CAR) T-cells have yielded impressive response rates in refractory/relapse B-cell acute lymphoblastic leukemia (B-ALL);however, most patients ultimately relapse due to poor CAR T-cell persistence or resistance of either CD19+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. Indeed, CD22-CAR T-cells have been clinically used in B-ALL patients, although relapse also occurs. Tcells engineered with a tandem CAR (Tan-CAR) containing in a single contruct both CD19 and CD22 scFvs, might be advantageus in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T-cells showed similar in vitro expansion than CD19-CAR T-cells with no increased of tonic signaling. CRISPR/Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples and patient-derived xenografts (PDXs). Strikingly, the robust anti-leukemic activity of the Tan-CAR was slightly more effective in controling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter B-all ; Cd19 ; Cd22 ; Patient-derived Xenografts ; Relapse ; Tandem Car T-cells
ISSN (print) / ISBN 1525-0016
e-ISSN 1525-0024
Zeitschrift Molecular Therapy
Quellenangaben Band: 30, Heft: 2, Seiten: 550-563 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen European Research Council
"Heroes hasta la medula" initiative
Marie Sklodowska Curie Fellowships
ISCIII (Sara Borrell)
Leo Messi Foundation
Obra Social La Caixa
Fundacion Uno entre Cienmil
Health Institute Carlos III (ISCIII/FEDER)
Spanish Ministry of Economy and Competitiveness
Spanish Association against Cancer (AECC)