{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["28"],"submitter":["Braun AH"],"pubmed_abstract":["CD3-targeted lentiviral vectors (CD3-LVs) mediate selective transduction of human T lymphocytes <i>in vitro</i> and <i>in vivo</i> while simultaneously activating the targeted cells. Previously, we have demonstrated that CD3-LV leads to downmodulation of the CD3:T cell receptor (TCR) complex. We therefore hypothesized that inhibition of CD3 phosphorylation by Src/Abl tyrosine kinase inhibitors such as dasatinib results in enhancement of gene delivery by T cell-targeted LVs. Indeed, dasatinib treatment of T cells prior to incubation with CD3-LV increased reporter gene delivery by 3- to 10-fold. Moreover, the presence of dasatinib enhanced selective transduction into non-activated target cells present in whole blood. When combined with delivery of the CD19-chimeric antigen receptor (CAR) gene, dasatinib increased CAR T cell numbers by close to 10-fold. Importantly, the short-term exposure of T cells to dasatinib during vector incubation did not interfere with tumor cell killing by the resulting CAR T cells and rather came along with less upregulated exhaustion markers and a more naive phenotype. Our data suggest that dasatinib prevents CD3-LV-induced phosphorylation and CD3:TCR intake, thereby increasing the amount of CD3-LV bound to the cell surface. This is the first description of dasatinib as transduction enhancer, an activity particularly relevant for CAR T cell generation with CD3-LV."],"journal":["Molecular therapy. Methods & clinical development"],"pagination":["90-98"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9801082"],"repository":["biostudies-literature"],"pubmed_title":["Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors."],"pmcid":["PMC9801082"],"pubmed_authors":["Braun AH","Frank AM","Ho N","Buchholz CJ"],"additional_accession":[]},"is_claimable":false,"name":"Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors.","description":"CD3-targeted lentiviral vectors (CD3-LVs) mediate selective transduction of human T lymphocytes <i>in vitro</i> and <i>in vivo</i> while simultaneously activating the targeted cells. Previously, we have demonstrated that CD3-LV leads to downmodulation of the CD3:T cell receptor (TCR) complex. We therefore hypothesized that inhibition of CD3 phosphorylation by Src/Abl tyrosine kinase inhibitors such as dasatinib results in enhancement of gene delivery by T cell-targeted LVs. Indeed, dasatinib treatment of T cells prior to incubation with CD3-LV increased reporter gene delivery by 3- to 10-fold. Moreover, the presence of dasatinib enhanced selective transduction into non-activated target cells present in whole blood. When combined with delivery of the CD19-chimeric antigen receptor (CAR) gene, dasatinib increased CAR T cell numbers by close to 10-fold. Importantly, the short-term exposure of T cells to dasatinib during vector incubation did not interfere with tumor cell killing by the resulting CAR T cells and rather came along with less upregulated exhaustion markers and a more naive phenotype. Our data suggest that dasatinib prevents CD3-LV-induced phosphorylation and CD3:TCR intake, thereby increasing the amount of CD3-LV bound to the cell surface. This is the first description of dasatinib as transduction enhancer, an activity particularly relevant for CAR T cell generation with CD3-LV.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Mar","modification":"2025-04-04T12:37:31.452Z","creation":"2025-04-04T12:37:31.452Z"},"accession":"S-EPMC9801082","cross_references":{"pubmed":["36620073"],"doi":["10.1016/j.omtm.2022.12.002"]}}