期刊
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
卷 13, 期 -, 页码 371-379出版社
CELL PRESS
DOI: 10.1016/j.omtm.2019.03.003
关键词
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资金
- European Union [667980]
- LOEWE Center for Cell and Gene Therapy Frankfurt - Hessische Ministerium fur Wissenschaft und Kunst (HMWK) [III L 5-518/17.004 [2013]]
- H2020 Societal Challenges Programme [667980] Funding Source: H2020 Societal Challenges Programme
Chimeric antigen receptor (CAR)-modified T cells have revealed promising results in the treatment of cancer, but they still need to overcome various hurdles, including a complicated manufacturing process. Receptor-targeted lentiviral vectors (LVs) delivering genes selectively to T cell subtypesmay facilitate and improve CAR T cell generation, but so far they have resulted in lower gene delivery rates than conventional LVs (vesicular stomatitis virus [VSV]-LV). To overcome this limitation, we studied the effect of the transduction enhancer Vectofusin-1 on gene delivery to human T cells with CD4- and CD8-targeted LVs, respectively, encoding a second-generation CD19-CAR in conjunction with a truncated version of the low-affinity nerve growth factor receptor (Delta LNGFR) as reporter. Vectofusin-1 significantly enhanced the gene delivery of CD4- and CD8-LVs without a loss in target cell selectivity and killing capability of the generated CAR T cells. Notably, delivery rates mediated by VSV-LV were substantially reduced by Vectofusin-1. Interestingly, a transient off-target signal in samples treated with Vectofusin-1 was observed early after transduction. However, this effect was not caused by uptake and expression of the transgene in off-target cells, but rather it resulted from cell-bound LV particles having Delta LNGFR incorporated into their surface. The data demonstrate that gene transfer rates in the range of those mediated by VSV-LVs can be achieved with receptor-targeted LVs.
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