CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.

Autor: Charitidis FT; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany., Adabi E; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany., Ho N; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany., Braun AH; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.; Deutsches Krebsforschungszentrum and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany., Tierney C; Characterisation and Comparability Laboratory, National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock, Dublin, A94 X099, Ireland., Strasser L; Characterisation and Comparability Laboratory, National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock, Dublin, A94 X099, Ireland., Thalheimer FB; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.; Frankfurt Cancer Institute (FCI), Goethe University, 60590, Frankfurt am Main, Germany., Childs L; Host-Pathogen Interactions, Paul-Ehrlich-Institut, 63225, Langen, Germany., Bones J; Characterisation and Comparability Laboratory, National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock, Dublin, A94 X099, Ireland.; School of Chemical and Bioprocess Engineering, University College Dublin, D04 V1W8, Belfield, Dublin, Ireland., Clarke C; Characterisation and Comparability Laboratory, National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock, Dublin, A94 X099, Ireland.; National Institute for Bioprocessing Research and Training, A94×099, Foster Avenue, Mount Merrion, Blackrock, Dublin, Ireland., Buchholz CJ; Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225, Langen, Germany.; Deutsches Krebsforschungszentrum and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.; Frankfurt Cancer Institute (FCI), Goethe University, 60590, Frankfurt am Main, Germany.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2023 Dec; Vol. 10 (35), pp. e2302992. Date of Electronic Publication: 2023 Oct 30.
DOI: 10.1002/advs.202302992
Abstrakt: Lentiviral vectors (LV) have become the dominant tool for stable gene transfer into lymphocytes including chimeric antigen receptor (CAR) gene delivery to T cells, a major breakthrough in cancer therapy. Yet, room for improvement remains, especially for the latest LV generations delivering genes selectively into T cell subtypes, a key requirement for in vivo CAR T cell generation. Toward improving gene transfer rates with these vectors, whole transcriptome analyses on human T lymphocytes are conducted after exposure to CAR-encoding conventional vectors (VSV-LV) and vectors targeted to CD8+ (CD8-LV) or CD4+ T cells (CD4-LV). Genes related to quiescence and antiviral restriction are found to be upregulated in CAR-negative cells exposed to all types of LVs. Down-modulation of various antiviral restriction factors, including the interferon-induced transmembrane proteins (IFITMs) is achieved with rapamycin as verified by mass spectrometry (LC-MS). Strikingly, rapamycin enhances transduction by up to 7-fold for CD8-LV and CD4-LV without compromising CAR T cell activities but does not improve VSV-LV. When administered to humanized mice, CD8-LV results in higher rates of green fluorescent protein (GFP) gene delivery. Also in vivo CAR T cell generation is improved in kinetics and tumor control, however to a moderate extent, leaving room for improvement by optimizing the rapamycin administration schedule. The data favor multi-omics approaches for improvements in gene delivery.
(© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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