Journal Article

DKFZ-2023-02204

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.

Charitidis, F. T. ; Adabi, E. ; Ho, N. ; Braun, A. H.DKFZ* ; Tierney, C. ; Strasser, L. ; Thalheimer, F. B. ; Childs, L. ; Bones, J. ; Clarke, C. ; Buchholz, C. J.DKFZ*

2023
Wiley-VCH Weinheim

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Please use a persistent id in citations: doi:10.1002/advs.202302992

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.

Keyword(s): in vivo gene delivery ; CAR T cells ; IFITM ; rapamycin ; receptor-targeted vectors ; scRNA-seq ; transduction enhancer

Note: 2023 Dec;10(35):e2302992

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Contributing Institute(s):

1. DKTK HD zentral (HD01)
2. DKTK Koordinierungsstelle Frankfurt (FM01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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