Impact of scFv on functionality and safety of third generation CD123 CAR T cells.
Fiche publication
Date publication
mai 2024
Journal
Cancer immunology research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Dr BOIDOT Romain, Pr DECONINCK Eric, Pr GARNACHE-OTTOU Francine, Dr GODET Yann, Dr DAGUINDAU Etienne, Dr GALAINE Jeanne, Dr ANGELOT-DELETTRE Fanny
Tous les auteurs :
Fredon M, Poussard M, Biichlé S, Bonnefoy F, Mantion CF, Seffar E, Renosi F, Bôle-Richard E, Boidot R, Chevrier S, Anna F, Loustau M, Caumartin J, Gonçalves-Venturelli M, Robinet E, Saas P, Deconinck E, Daguindau E, Roussel X, Godet Y, Adotévi O, Angelot-Delettre F, Galaine J, Garnache-Ottou F
Lien Pubmed
Résumé
Chimeric antigen receptor (CAR) T cells express an extracellular domain consisting of a single-chain fragment variable (scFv) targeting a surface tumor-associated antigen. scFv selection should involve safety profiling with evaluation of the efficacy/toxicity balance, especially when the target antigen also is expressed on healthy cells. Here, to assess differences in terms of efficacy and on-target/off-tumor effects, we five different CARs targeting CD123 by substituting only the scFv. In in vitro models, T cells engineered to express three of these five CD123 CARs were effectively cytotoxic on leukemic cells without increasing lysis of monocytes or endothelial cells. Using the IncuCyte® system, we confirmed the low cytotoxicity of CD123 CAR T cells on endothelial cells. Hematotoxicity evaluation using progenitor culture and CD34 cell lysis showed that two of the five CD123 CAR T cells were less cytotoxic on hematopoietic stem cells. Using a humanized mouse model, we confirmed that CD123- cells were not eliminated by the CD123 CAR T cells. Two CD123 CAR T cells reduced tumor infiltration and increased overall survival of mice in three in vivo models of blastic plasmacytoid dendritic cell neoplasm. In an aggressive version of this model, bulk RNA sequencing analysis showed that these CD123 CAR T cells upregulated genes associated with cytotoxicity and activation/exhaustion a few days after the injection. Together, these results emphasize the importance of screening different scFvs for the development of CAR constructs to support selection of cells with the optimal risk-benefit ratio for clinical development.
Référence
Cancer Immunol Res. 2024 05 31;: