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• W1566351742 abstract "Lentiviral‐based vectors are effective and promising tools for the generation ofcell mediated immunity. Multiple studies have demonstrated that subcutaneousinjection of lentivectors encoding tumour antigens results in induction of strong CTLresponses and often in tumour killing. However, integration of lentivectors into humangenomic DNA poses a risk of insertional mutagenesis. Indeed, this possibility has beenhighlighted by gene therapy trials that resulted in the development of T cell leukaemiain several patients. For this reason, non‐integrating lentiviral vectors (NILVs) have beendeveloped as a safer alternative for gene delivery.The first part of this thesis demonstrates that lentivectors carrying multiplemutations preventing integration are effective vaccines. Subcutaneous injection ofthese vectors resulted in induction of systemic dose‐dependant CD8+ T‐cell responsesto the encoded antigen. The duration of the persistence of antigen presentation wasmeasured using transfer of OT1 transgenic T cells into previously immunized mice.Measuring expansion of those cells revealed that the antigen was present andpresented for at least 30 days. CD8+ T‐cell responses were further enhanced byaddition of dendritic cell (DC) stimulators: p38 MAP kinase and NF‐κB stimulators.These activators led to a more rapid response peaking at day 7. Finally, NILVsexpressing the antigen and DC activators were tested in a tumour therapy model andwere found to be effective.The second part of this thesis focused on altering DC‐T cell interactions toenhance responses to immunization by lentivector‐mediated knockdown of PDL1 onDCs. The analysis of DCs infected with anti‐PDL1 shRNA showed that knocking downthis molecule drives DCs towards a mature phenotype. The influence of PDL1knockdown was assessed on co‐cultured T cells. The absence of PDL1 enhanced theirproliferation and reduced antigenic stimulation induced TCR complex degradation. DCstransduced with lentivectors expressing PDL1 shRNA were also tested in vaccinationand tumour therapy." @default.
• W1566351742 created "2016-06-24" @default.
• W1566351742 creator A5088666814 @default.
• W1566351742 date "2012-01-28" @default.
• W1566351742 modified "2023-09-24" @default.
• W1566351742 title "Lentivector based gene transfer for immunotherapy – application of integration deficient vectors and PDL1knockdown as tools to manipulate immune responses" @default.
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