Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors.

Autor:	Braun AH; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany., Frank AM; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Ho N; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany., Buchholz CJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, Germany.; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2022 Dec 07; Vol. 28, pp. 90-98. Date of Electronic Publication: 2022 Dec 07 (Print Publication: 2023).
DOI:	10.1016/j.omtm.2022.12.002
Abstrakt:	CD3-targeted lentiviral vectors (CD3-LVs) mediate selective transduction of human T lymphocytes in vitro and in vivo 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. Competing Interests: C.J.B., A.M.F., and A.H.B. are inventors of a patent describing the use of dasatinib as a transduction enhancer. (© 2022 The Authors.)
Databáze:	MEDLINE
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