Descripción del proyecto
Aprovechamiento de la vía de la hipoxia de los linfocitos T en la inmunoterapia oncológica
Una respuesta clínica sólida a la inmunoterapia depende de la capacidad de los linfocitos T para desarrollar respuestas efectoras persistentes y evitar la toxicidad. Varios avances en inmunoterapia se han mostrado prometedores en ensayos clínicos, al introducir inhibidores de puntos de control inmunitarios y tratamientos con linfocitos T adoptivos autólogos. El entorno específico del tumor afecta a la respuesta inmunitaria y al éxito de los tratamientos, al crear una disminución de la oxigenación, una vascularización anómala y una alteración de la disponibilidad de nutrientes. El proyecto NextGen IO, financiado con fondos europeos, se centra en el descubrimiento de dianas inmunológicas y el desarrollo de fármacos para el tratamiento oncológico utilizando las oportunidades que ofrece la vía de la hipoxia en los linfocitos T. Entre sus objetivos se incluyen el desarrollo de una nueva minimolécula moduladora de la respuesta hipóxica en los linfocitos T, el descubrimiento de dianas centradas en las modificaciones epigenéticas impulsadas por la hipoxia y los tratamientos con linfocitos T para tumores sólidos hipóxicos.
Objetivo
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.
Ámbito científico
- 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
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
48160 DERIO VIZCAYA
España