| Title: |
Development and evaluation of a novel vaccine platform for the treatment of melanoma ; Développement et évaluation d'une plateforme vaccinale novatrice pour le traitement du mélanome |
| Authors: |
Besson, Solène |
| Contributors: |
Institut de biologie structurale (IBS - UMR 5075); Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA); Université Grenoble Alpes 2020-.; Pascal Fender |
| Source: |
https://theses.hal.science/tel-04054734 ; Biochimie, Biologie Moléculaire. Université Grenoble Alpes [2020-.], 2022. Français. ⟨NNT : 2022GRALV072⟩. |
| Publisher Information: |
CCSD |
| Publication Year: |
2022 |
| Collection: |
Université Grenoble Alpes: HAL |
| Subject Terms: |
Nanoparticle; Immuno-Oncology; Vector; Cancer; Adenovirus; Nanoparticule; Immunotherapie; Vecteur; [SDV.BBM]Life Sciences [q-bio]/Biochemistry; Molecular Biology; [SDV.CAN]Life Sciences [q-bio]/Cancer; [SDV.IMM]Life Sciences [q-bio]/Immunology |
| Description: |
Virus like particles (VLPs) are versatile protein-based platforms which can be used as vaccine platform mainly in infectiology. In the present work we used adenoviruses dodecahedrons to display either short epitopes or a large tumor antigen. These non-infectious but immunogenic structures are formed during the adenovirus replication cycle, and have been modified to create a versatile platform named ADDomer (ADenovirus Dodecamer). Recently, it has been shown that ADDomers displaying a Chikungunya virus epitope successfully induced an anti-epitopic response in mice.Based on these results, this project aims at adapting the ADDomer platform to develop a cancer vaccine for melanoma. ADDomers displaying melanoma epitopes/antigens have successfully been produced and characterized. Epitopes can directly be genetically inserted inside the ADDomers’ exposed loops and are therefore exposed on the ADDomers’ surface. For antigens, the autocatalytic system SpyTag/SpyCatcher was adapted in order to covalently fix antigens on the ADDomers’ surface.Once the ADDomers were fully produced and characterized, we explored for the first time the immunogenicity of these ADDomers and their impact on human dendritic cell (DC) subsets’ features. We first demonstrated that A2L/MelA-ADDomers (ADDomers displaying human melanoma either epitope or antigen) displayed a strong immune-stimulating potential on human DC subsets (cDC2s, cDC1s, pDCs), which were able to internalize and cross-present tumor antigen, and subsequently cross-prime antigen-specific T-cell responses. To further limit off-target effects and enhance DC targeting, we engineered specific ligands to de-target untargeted cells (epithelial cells) and improve DCs’ addressing.Finally, we evaluated the ADDomers’ ability to control melanoma B16-OVA growth in mice. A set of adjuvants was screened showing that Poly I:C was well-suited to generate a homogenous cellular and humoral response against the desired epitopes. In a prophylactic setting, vaccination with the ADDomers displaying ... |
| Document Type: |
doctoral or postdoctoral thesis |
| Language: |
French |
| Relation: |
NNT: 2022GRALV072 |
| Availability: |
https://theses.hal.science/tel-04054734; https://theses.hal.science/tel-04054734v1/document; https://theses.hal.science/tel-04054734v1/file/BESSON_2022_archivage.pdf |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.28DC34D2 |
| Database: |
BASE |