Description du sujet de thèse

Cellular immunotherapies, particularly CAR-T therapies, involve removing the patient's T lymphocytes, modifying them ex vivo (in the laboratory) to express a chimeric receptor specific to a tumor antigen (CAR), and then reinjecting them so that they exert their cytotoxic activity specifically against tumor cells expressing the antigen. These therapies have shown notable efficacy in certain cancers (particularly hematological cancers), but have a number of limitations, including the duration, the very high cost and the technicality of the process of ex vivo genetic modification of the patient's cells, certain side effects after injection of the modified cells and low efficacy in solid tumors. The in vivo strategy aims to inject a vector (often viral or nanoparticle) directly into the patient's body that will "program" the T lymphocytes on site to express this CAR, without removing them from the body. The advantages of in vivo programming would be lower cost, faster processing, and more standardized, ready-to-use processes. The in vivo strategy aims to inject a vector (often viral or nanoparticle) directly into the patient's body that will "program" the T lymphocytes on site to express this CAR, without removing them from the body. The advantages of in vivo programming would be lower cost, faster processing, and more standardized, ready-to-use processes.In addition to viral vectors carrying and integrating the CAR gene (immunogenicity and gene insertion issues), research is turning to messenger RNA vectors such as lipid nanoparticles (LNPs) used for mRNA vaccines (COVID vaccines) and surface modified to target T cells. As part of the CARN project of the PEPR Biotherapies and Bioproduction of Innovative Therapies, we have proposed hybrid mRNA vectors resulting from the fusion of LNPs loaded with mRNA, with extracellular vesicles derived from mesenchymal stromal cells. These hybrid vectors could combine the advantages of LNPs in terms of mRNA encapsulation and functionalization with those of extracellular vesicles, as an intercellular communication system capable of targeting recipient cells and efficiently delivering their contents without immunogenic effect. Many challenges remain to achieve reproducible hybridization of the two vectors while ensuring high mRNA loading efficiency. The objective of this thesis will be to develop hybrid extracellular vesicles, loaded with mRNA encoding a CAR, and capable of specifically targeting T cells after in vivo injection.

Contexte de travail

-The new multidisciplinary unit NABI (Nanomedicine, Extracellular Biology, Integratome and Health Innovations), on the Saint Germain Campus of the Université Paris Cité (45 rue des Saints Pères, 75006 Paris) was created on January 1, 2025 and brings together around 75 collaborators: physicists, biologists, pharmacists, engineers and doctors, including around thirty permanent staff, under the supervision of the CNRS, INSERM and the Université Paris Cité. The scientific objectives of NABI are to develop new therapies based on biological nano-objects (extracellular vesicles) or synthetic nano-objects (activatable metal nanoparticles) for the delivery of personalized therapies for difficult-to-treat pathologies.730 / 5,000
NABI's scientific objectives are to develop new therapies based on biological (extracellular vesicles) or synthetic (activatable metal nanoparticles) nano-objects for the delivery of personalized therapies for difficult-to-treat pathologies. The study of nano-objects in biological fluids requires transdisciplinary approaches (physics, engineering, cellular and molecular biology, immunology, etc.) up to clinical practice and dedicated technical and analytical means (super-resolution microscopy, nanoprobes, microfluidics, etc.) as well as systematic multimodal and multi-scale exploration whose analysis uses AI.
These innovative methodologies are developed within NABI and the industrial integrator IVETh, a technology hub dedicated to the characterization, bioproduction, and engineering of extracellular vesicles and nanovectors for diagnostics and personalized therapies. The agent will join the multidisciplinary "Nanobiotherapies" team as part of the CARN project of the PEPR Biotherapies and Bioproduction of Innovative Therapies. The position is located in a sector covered by the protection of scientific and technical potential (PPST), and therefore requires, in accordance with regulations, that your arrival be authorized by the competent authority of the MESR.hese innovative methodologies are

Le poste se situe dans un secteur relevant de la protection du potentiel scientifique et technique (PPST), et nécessite donc, conformément à la réglementation, que votre arrivée soit autorisée par l'autorité compétente du MESR.

Contraintes et risques

Biological hazard