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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)

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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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords B-all ; Cd19 ; Cd22 ; Patient-derived Xenografts ; Relapse ; Tandem Car T-cells

ISSN (print) / ISBN 1525-0016

e-ISSN 1525-0024

Journal Molecular Therapy

Quellenangaben Volume: 30, Issue: 2, Pages: 550-563

Publisher Nature Publishing Group

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)

Grants 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)