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

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...

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Detalles Bibliográficos
Autores: Romecín, Paola Alejandra, Zanetti, Samanta Romina, Velasco-Hernandez, Talia, Gutierrez-Agüera, Francisco, Díaz, Víctor M., Roca-Ho, Heleia, Sánchez-Martínez, Diego, Tirado Cabrera, Néstor, Baroni, Matteo Libero, Petazzi, Paolo, Torres-Ruiz, Raúl, Molina, Òscar, Bataller Torralba, Alex, Fuster, José Luis, Ballerini, Paola, Juan, Manel, Jeremias, Irmela, Bueno, Clara, Menéndez Buján, Pablo
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/218503
Acceso en línea:https://hdl.handle.net/2445/218503
Access Level:acceso abierto
Palabra clave:Limfòcits
Antígens
Immunoteràpia
Lymphocytes
Antigens
Immunotheraphy
Descripción
Sumario: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. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous 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 to CD19-CAR T cells with no increase in 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 antileukemic activity of the Tan-CAR was slightly more effective in controlling 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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