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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Dec 20, 2023 |
| Title |
CAR gene delivery by T-cell targeted lentiviral vectors is enhanced by rapamycin induced reduction of antiviral mechanisms |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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. Towards improving gene transfer rates with these vectors, we conducted whole transcriptome analyses on human T lymphocytes after exposure to CAR-encoding conventional vector VSV-LV, and vectors targeted to CD8+ (CD8-LV) or CD4+ T cells (CD4-LV). Genes related to quiescence and antiviral restriction were 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) was achieved with rapamycin as verified by mass spectrometry (LC-MS). Strikingly, rapamycin enhanced transduction by up to 7-fold for CD8-LV and CD4-LV without compromising CAR T cell activities, but did not improve VSV-LV. When administered to humanized mice, CD8-LV resulted in higher rates of GFP gene delivery as well as faster in vivo CAR T cell generation and tumor control. The data favors multi-omics approaches for improvements in gene delivery.
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| Overall design |
scRNA-seq analysis of lentiviral vector generated CAR T cells
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| Contributor(s) |
Charitidis FT, Adabi E, Ho N, Braun AH, Tierney C, Strasser L, Thalheimer FB, Childs L, Bones J, Clarke C, Buchholz CJ |
| Citation(s) |
37904721 |
| BioProject |
PRJNA950024 |
| Submission date |
Apr 03, 2023 |
| Last update date |
Dec 21, 2023 |
| Contact name |
Christian J. Buchholz |
| E-mail(s) |
christian.buchholz@pei.de
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| Organization name |
Paul Ehrlich Institut
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| Street address |
Paul-Ehrlich-Strasse 51-59
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| City |
Langen |
| State/province |
Hessen |
| ZIP/Postal code |
63225 |
| Country |
Germany |
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| Platforms (2) |
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| Samples (13)
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| Supplementary file |
Size |
Download |
File type/resource |
| GSE228824_RAW.tar |
77.8 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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