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- W821370183 abstract "The ability to manipulate the immune system to induce protection againsttumour, is one of the most fascinating challenges in immunology. In thisregard, TCR gene transfer is an attractive and powerful strategy to generatehigh numbers of tumour antigen-specific T cells for adoptive transfer treatment.This thesis describes the optimization of lentiviral vectors for TCR genetransfer in the absence of polyclonal activation of the transduced T cells, whichmay improve subsequent adoptive T cell therapy. The murinised and codonoptimised chains of an HLA-A*0201-restricted TCR specific for Wilms` tumourantigen 1 were cloned in lentiviral vector constructs improved with a Leadersequence and the WPRE elements for redirecting T cells specificity. Theeffects of common gamma chain receptor cytokines IL-2, IL-7, IL-15 and IL-21were investigated using WT1 TCR-transduced T cells for transductionefficiency, proliferative potential, phenotype and functional activity in responseto cognate antigen. Although all cytokines tested allowed transduction,stimulations with IL-15 and IL-15 with IL-7 or with IL-21 promoted a higherefficiency. Expression analysis of CD28 and CD62L showed an important roleof IL-21 in maintenance of a naive phenotype. In addition, all cytokinespromoted maintenance of “quality” of T cells as shown by co-expression of IL-2, IFN-γ and TFN-α after specific stimulation. To further sustain the in vitroresults, several in vivo models were tested. Consistently, using F5 transgenicmice recognizing the NP peptide presented on EL4-NP cell line, IL-15 with IL-21 exposed CD8+ T cells were able to efficiently protect against tumour and topersist longer in tumour bearing mice compared to IL-2 treated T cells.Because previous reports demonstrated that efficient LN homing of T cellcorrelates with efficient tumour protection in vivo, an imaging approach tostudy the molecular signalling in vivo during T cell activation in the LN hasbeen developed. In conclusion, in this thesis, it is demonstrated that lentiviraltransduction of cytokine exposed T cell can improve gene therapy approach ofadoptive therapy." @default.
- W821370183 created "2016-06-24" @default.
- W821370183 creator A5026544482 @default.
- W821370183 date "2010-09-01" @default.
- W821370183 modified "2023-09-26" @default.
- W821370183 title "Lentiviral TCR gene transfer for tumour immunotherapy" @default.
- W821370183 hasPublicationYear "2010" @default.
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