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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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