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Développement de l'immunothérapie anti-tumorale médiée par vecteur bactérien vivant basé sur le système de sécrétion de type III de Pseudomonas aeruginosa

Abstract : Due to the endowed effective ability to deliver antigen to cytoplasm of APCs in vivo, T3SS based attenuated bacterial vectors attracted more and more attention for their potential interest in cancer vaccine development. Pseudomonas aeruginosa est un pathogène opportuniste responsable d'infections graves chez les personnes immunodéprimées, les grands brûlés et les patients atteints de la mucoviscidose. Cette pathogénicité repose sur de nombreux facteurs de virulence dont le système de sécrétion de type III (SSTT). In our previous work, the potential of attenuated P. aeruginosa strains as the carriers for anti-tumor vaccination purpose has been reported. In this work, we would like to strengthen P. aeruginosa T3SS based vaccine vectors and direct the development of these bacterial vectors toward clinical applications. First, the performance of these bacterial vectors has been improved in different murine cancer models by: 1) adding one CD4+ Th epitope to vectors; 2) applying bi-antigen expression pattern to vectors; 3) constructing potential humoral response inducing vectors. Second, the therapeutic performance of bacterial vector has been optimized by modulating injection frequency and interval and then be confirmed in murine tumor models. Third, one clinically applicable candidate has been generated by adapting one totally avirulent P. aeruginosa mutant (CHA-OAL) in a chemically defined medium and the poor infectivity of this new strain has been overcome by vaccinations at multiple loci. Fourth, the potential of bacterial vector for human immunotherapy has been further evaluated in one first level humanized mice (HHD) model. Finally, we observed that the pre-existing anti-vector immunity didn't impair the vaccination efficiency of bacteria vector. Taken together, our results highlight the potentials of our live attenuated P. aeruginosa vectors for applications in relevant clinical trials.
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https://tel.archives-ouvertes.fr/tel-00767285
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Submitted on : Wednesday, December 19, 2012 - 4:32:17 PM
Last modification on : Thursday, November 19, 2020 - 3:56:08 PM
Long-term archiving on: : Wednesday, March 20, 2013 - 11:31:51 AM

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Yan Wang. Développement de l'immunothérapie anti-tumorale médiée par vecteur bactérien vivant basé sur le système de sécrétion de type III de Pseudomonas aeruginosa. Médecine humaine et pathologie. Université de Grenoble, 2012. Français. ⟨NNT : 2012GRENS010⟩. ⟨tel-00767285⟩

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