TY  - JOUR
AU  - Charitidis, Filippos T
AU  - Adabi, Elham
AU  - Ho, Naphang
AU  - Braun, Angela H
AU  - Tierney, Ciara
AU  - Strasser, Lisa
AU  - Thalheimer, Frederic B
AU  - Childs, Liam
AU  - Bones, Jonathan
AU  - Clarke, Colin
AU  - Buchholz, Christian J
TI  - CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.
JO  - Advanced science
VL  - 10
IS  - 35
SN  - 2198-3844
CY  - Weinheim
PB  - Wiley-VCH
M1  - DKFZ-2023-02204
SP  - e2302992
PY  - 2023
N1  - 2023 Dec;10(35):e2302992
AB  - 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.
KW  -  in vivo gene delivery (Other)
KW  - CAR T cells (Other)
KW  - IFITM (Other)
KW  - rapamycin (Other)
KW  - receptor-targeted vectors (Other)
KW  - scRNA-seq (Other)
KW  - transduction enhancer (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37904721
DO  - DOI:10.1002/advs.202302992
UR  - https://inrepo02.dkfz.de/record/285061
ER  -