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

Zanetti, Samanta Romina; Velasco-Hernandez, Talia; Gutierrez-Aguera, Francisco; Diaz, Victor M.; Romecin, Paola Alejandra; Roca-Ho, Heleia; Sanchez-Martinez, Diego; Tirado, Nestor; Baroni, Matteo Libero; Petazzi, Paolo; Torres-Ruiz, Raul; Molina, Oscar; Bataller, Alex; Fuster, Jose Luis; Ballerini, Paola; Juan, Manel; Jeremias, Irmela; Bueno, Clara und Menendez, Pablo (2022): A novel and efficient tandem CD19-and CD22-directed CAR for B cell ALL. In: Molecular Therapy, Bd. 30, Nr. 2: S. 550-563

Abstract

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 panB 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. TanCAR 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 TanCAR was slightly more effective in controlling the disease in long-termfollow-up PDXmodels. 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1525-0016
• Sprache: Englisch