Description du projet
Une stratégie «d’ajustement» pour les lymphocytes T en fonction des besoins cliniques
La thérapie adoptive par lymphocytes T constitue une approche révolutionnaire dans différentes interventions cliniques, dont l’immunothérapie cancéreuse spécifique à la cible et la lutte contre les infections chroniques, l’auto‑immunité et les réponses immunitaires non souhaitées après une transplantation d’organe. Actuellement, ses applications cliniques sont entravées par l’acquisition de la sénescence durant la phase d’expansion des lymphocytes T in vitro, et par la plasticité fonctionnelle des lymphocytes T qui, après transfusion, peut entraîner un changement fonctionnel de l’effet recherché. Les acteurs épigénétiques tels que la méthylation de l’ADN contribuent à la différenciation des lymphocytes T, créant une possibilité unique de stabiliser le développement et la fonction des cellules. Le projet EpiTune, financé par l’UE, entend doter les lymphocytes T de propriétés qui garantiraient la réussite et la sécurité de leur application thérapeutique, dont leur réglage fonctionnel en fonction des besoins cliniques. L’idée est d’améliorer la thérapie par lymphocytes T en modifiant directement l’épigénome.
Objectif
"Adoptive T cell therapy is a promising approach in various clinical settings, from target-specific immune reconstitution fighting cancer and chronic infections to combating undesired immune reactivity during auto-immunity and after organ transplantation.
However, its clinical application is currently hampered by: 1) the acquisition of senescence during the required in vitro expansion phase of T cells which limits their survival and fitness after infusion into the patient, and 2) the functional plasticity of T cells, which is sensitive to the inflammatory environment they encounter after transfusion and which might result in a functional switch from the desired effect (e.g. immunosuppressive) to the opposite one (pro-inflammatory).
I want to tackle these obstacles from a new molecular angle, utilizing the profound impact of epigenetic mechanisms on the senescence process as well as on the functional imprinting of T lymphocytes. Epigenetic players such as DNA methylation essentially contribute to T cell differentiation and harbor the unique prospect to imprint a stable developmental and functional state in the genomic structure of a cell, as we could recently show in our basic immune-epigenetic studies. Therefore, I here propose to equip T lymphocytes with the required properties for their successful and safe therapeutic application, including their functional fine-tuning according to the clinical need by directed modifications of the epigenome
('Epi-tuning').
To reach these goals I want: 1) to reveal strategies for the directed manipulation of the epigenetically-driven mechanism of cellular senescence and 2) to apply state-of-the-art CRISPR/Cas9-mediated epigenetic editing approaches for the imprinting of a desired functional state of therapeutic T cell products. These innovative epigenetic ""one-shot"" manipulations during the in vitro expansion phase should advance T cell therapy towards improved efficiency, stability as well as safety."
Champ scientifique
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Programme(s)
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Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
10117 Berlin
Allemagne