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A synthetic biology approach to engineering exhaustion-free T cell therapies. Uncovering and counteracting biomechanical triggers of T cell dysfunction in the tumour microenvironment.

Descrizione del progetto

Verso terapie anticancro più sofisticate

Le cellule T del recettore dell’antigene chimerico (CAR, chimeric antigen receptor) sono emerse come potenti armi antitumorali, dimostrando una grande efficacia clinica contro le neoplasie ematologiche. Tuttavia, la prolungata stimolazione antigenica ne ha ostacolato l’efficacia contro i tumori solidi. Il progetto Tex-Mex, finanziato dall’UE, studierà i fattori scatenanti biomeccanici del microambiente tumorale sulla stimolazione e disfunzione prolungata delle cellule T. I ricercatori utilizzeranno un modello microfluidico che riassume tutti i parametri noti dell’esaurimento delle cellule T e aggiunge una dimensione biomeccanica. I risultati contribuiranno ad affrontare le strozzature della terapia CAR-T associata all’esaurimento delle cellule T e ad avanzare verso una terapia anticancro universale.

Obiettivo

Cancer is the second leading cause of death in the European Union, having killed 1.4 million people in 2018 alone. Chimeric antigen receptor (CAR) T cell therapy is a ground-breaking cancer treatment that has demonstrated striking results in fighting blood cancers. However, T cell exhaustion, a process that results in the progressive development of lymphocyte dysfunction due to prolonged antigen stimulation in cancer, chronic inflammation or infection, has been a major obstacle in translating CAR T cell therapy to solid tumours. The solid tumour microenvironment is biomechanically distinct from physiological conditions, being characterized by higher interstitial pressures, higher stiffness and a distinctive vascular architecture. While biochemical triggers for T cell exhaustion have been well characterized, biomechanical influences are understudied. This project seeks to (i) use a microfluidic model to add the biomechanical dimension to our current understanding of the development of T cell exhaustion and (ii) use synthetic biological approaches to engineer “biomechanosensor-actuator devices”. These will be intracellular systems based on synthetic biological circuits that will integrate biochemical and biomechanical cues of T cell exhaustion and trigger genetic pathways to counteract the development of dysfunctional phenotypes. Integrating the biomechanical and biochemical dimensions will yield a more sophisticated cell therapy platform to neutralize T cell exhaustion. Ultimately this would provide a safer, more effective and universal treatment for cancer by preventing T cell exhaustion and immune escape.

Campo scientifico (EuroSciVoc)

Parole chiave

Programma(i)

Argomento(i)

Meccanismo di finanziamento

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Invito a presentare proposte

(si apre in una nuova finestra) H2020-MSCA-IF-2020

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Coordinatore

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Contributo netto dell'UE
€ 171 473,28
Costo totale
€ 171 473,28