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@ARTICLE{Charitidis:285061,
author = {F. T. Charitidis and E. Adabi and N. Ho and A. H. Braun$^*$
and C. Tierney and L. Strasser and F. B. Thalheimer and L.
Childs and J. Bones and C. Clarke and C. J. Buchholz$^*$},
title = {{CAR} {G}ene {D}elivery by {T}-cell {T}argeted {L}entiviral
{V}ectors is {E}nhanced by {R}apamycin {I}nduced {R}eduction
of {A}ntiviral {M}echanisms.},
journal = {Advanced science},
volume = {10},
number = {35},
issn = {2198-3844},
address = {Weinheim},
publisher = {Wiley-VCH},
reportid = {DKFZ-2023-02204},
pages = {e2302992},
year = {2023},
note = {2023 Dec;10(35):e2302992},
abstract = {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.},
keywords = {in vivo gene delivery (Other) / CAR T cells (Other) / IFITM
(Other) / rapamycin (Other) / receptor-targeted vectors
(Other) / scRNA-seq (Other) / transduction enhancer (Other)},
cin = {HD01 / FM01},
ddc = {624},
cid = {I:(DE-He78)HD01-20160331 / I:(DE-He78)FM01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:37904721},
doi = {10.1002/advs.202302992},
url = {https://inrepo02.dkfz.de/record/285061},
}