%0 Journal Article
%A Charitidis, Filippos T
%A Adabi, Elham
%A Ho, Naphang
%A Braun, Angela H
%A Tierney, Ciara
%A Strasser, Lisa
%A Thalheimer, Frederic B
%A Childs, Liam
%A Bones, Jonathan
%A Clarke, Colin
%A Buchholz, Christian J
%T CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.
%J Advanced science
%V 10
%N 35
%@ 2198-3844
%C Weinheim
%I Wiley-VCH
%M DKFZ-2023-02204
%P e2302992
%D 2023
%Z 2023 Dec;10(35):e2302992
%X 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.
%K  in vivo gene delivery (Other)
%K CAR T cells (Other)
%K IFITM (Other)
%K rapamycin (Other)
%K receptor-targeted vectors (Other)
%K scRNA-seq (Other)
%K transduction enhancer (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:37904721
%R 10.1002/advs.202302992
%U https://inrepo02.dkfz.de/record/285061