Description du projet
Exploiter la voie de l’hypoxie des lymphocytes T dans l’immunothérapie du cancer
Une réponse clinique robuste à l’immunothérapie dépend de la capacité des lymphocytes T à développer des réponses effectrices persistantes et à éviter la toxicité. Plusieurs développements en matière d’immunothérapie se sont révélés prometteurs lors des essais cliniques, notamment les inhibiteurs de points de contrôle immunitaire et les thérapies autologues adoptives à base de lymphocytes T. L’environnement spécifique de la tumeur affecte la réponse immunitaire et le succès des traitements en créant une oxygénation réduite, une vascularisation aberrante et une disponibilité altérée des nutriments. Le projet NextGen IO, financé par l’UE, se concentre sur la découverte de cibles immuno-oncologiques et le développement de médicaments pour le traitement du cancer en utilisant les possibilités offertes par la voie de l’hypoxie dans les lymphocytes T. Les objectifs comprennent le développement d’une nouvelle petite molécule modulant la réponse hypoxique dans les lymphocytes T, la découverte de cibles axées sur les modifications épigénétiques induites par l’hypoxie et les thérapies par lymphocytes T pour les tumeurs hypoxiques solides.
Objectif
NextGen_IO has a core focus on immuno-oncology, specifically on target discovery and drug development, to exploit several opportunities that the hypoxia pathway in T cells offers for the treatment of cancer. It is well recognised that the clinical response of immunotherapies depends on the ability of T-cells to mount an effective effector response, persist in treated patients and avoid exhaustion and toxicities. Several approaches to immunotherapy have shown promise in clinical trials, especially the use of immune checkpoint inhibitors and, more recently, autologous adoptive T-cell therapies. However, current state-of-the-art immunotherapies are only effective in a small fraction of patients, offering a medical need to be addressed in several cancer types. Importantly, the tumor microenvironment has specific features that impact the immune response, including decreased oxygenation, aberrant vascularization and altered nutrient availability; all these influence the success of immunotherapies. During the last 10 years, my research has been focused on elucidating the role of the oxygen sensing machinery in T cell function, and the link of hypoxia-driven metabolism and epigenetic modifications with T cell differentiation into effector and memory T cells within the context of cancer immunotherapy. The current proposal aims to exploit these previous findings with a multi-disciplinary strategy, to deliver several early-stage drug discovery outputs.
The main objectives are:
1. Development of a novel small molecule inhibitor to modulate the hypoxic response in T cells.
2. Therapeutic target discovery in T cells, focused on hypoxia-driven epigenetic modifications.
3. Development of hypoxia-inducible molecular switches for adoptive T cell therapy.
Successful completion of the project will allow me to further innovate and consolidate my position as a leader in this field, harness this pathway for therapeutic potential and explore potential combinatorial approaches.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
- medical and health sciencesmedical biotechnologycells technologies
- natural sciencesbiological sciencesgeneticsepigenetics
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
48160 DERIO VIZCAYA
Espagne