Descrizione del progetto
Una strategia di «messa a punto» dei linfociti T in base alle esigenze cliniche
La terapia adottiva a base di cellule T rappresenta un approccio rivoluzionario in vari interventi clinici, tra cui l’immunoterapia antitumorale specifica per il bersaglio e la lotta contro le infezioni croniche, le malattie autoimmuni e le risposte immunitarie indesiderate in seguito al trapianto d’organo. Attualmente, le sue applicazioni cliniche sono rese più complesse dall’acquisizione della senescenza durante la fase di espansione in vitro delle cellule T e dalla plasticità funzionale delle cellule T che, dopo la trasfusione, potrebbero comportare una variazione funzionale rispetto all’effetto desiderato. I fattori epigenetici, quali la metilazione del DNA, contribuiscono alla differenziazione delle cellule T, originando una possibilità unica di stabilizzare lo sviluppo e la funzionalità delle cellule. Il progetto EpiTune, finanziato dall’UE, è volto a dotare i linfociti T di proprietà in grado di garantire la riuscita e la sicurezza della loro applicazione terapeutica, compresa la loro messa a punto funzionale in base alle esigenze cliniche. L’idea è quella di migliorare la terapia a base di cellule T tramite modifiche dirette dell’epigenoma.
Obiettivo
"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."
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
10117 Berlin
Germania