Descrizione del progetto
Riprogrammare l’esaurimento delle cellule T mediante l’utilizzo di circuiti logici sintetici
Le cellule T, parte integrante del sistema immunitario, riconoscono e rispondono a specifiche porzioni di particelle estranee o di molecole cancerogene alterate. Tali linfociti eliminano direttamente gli agenti patogeni e le cellule tumorali e inviano messaggi al resto del sistema immunitario per migliorarne la risposta. Lo sfruttamento di queste cellule nelle terapie antitumorali ha dimostrato un’efficacia limitata nel trattamento dei tumori solidi principalmente a causa del cosiddetto processo di esaurimento delle cellule T. I linfociti T «esauriti» iniziano a produrre quantità molto inferiori di proteine in grado di stimolare il sistema immunitario e la loro capacità di uccidere le cellule tumorali viene limitata. Il progetto T-FITNESS, finanziato dall’UE, svilupperà un nuovo approccio volto a rendere le cellule T refrattarie all’esaurimento mediante l’utilizzo di circuiti logici sintetici basati sul microRNA allo scopo di ristabilire le reti trascrizionali responsabili dello stesso.
Obiettivo
Cell and gene therapies offer a massive paradigm shift from current treatment options and hold the potential to cure previously untreatable diseases. Naturally-occurring and genetically modified T cells with chimeric antigen (CAR) or T cell receptors (TCR) have demonstrated remarkable curative capacities against advanced hematologic malignancies but have shown limited efficacy in treating solid tumors. Major barriers hindering the full antitumor potential of T cells are the immunosuppressive signals and persisting antigenic stimuli within the tumor microenvironment that inexorably push T cells into a highly dysfunctional state called “exhaustion”. Herein, we propose a groundbreaking technology, T-FITNESS, which will enable antitumor T cells to become refractory to exhaustion. At the core of the platform are microRNA (miRNA)-based synthetic logic circuits capable of rewiring the transcriptional networks orchestrating T cell exhaustion. By harnessing the power of CRISPR/Cas genome editing, we will integrate sensors of miRNAs upregulated in exhausted cells into untranslated regions of one or more transcription factors driving T cell exhaustion, to enable their fine-tuned downregulation. We will validate the reprogramming efficacy of T-FITNESS by performing extensive functional analyses in vitro and in vivo and advance the best circuits towards the clinic by developing an automated cGMP-compliant manufacturing process for point-of-care production of T-FITNESS-edited CAR-T cells. To develop this innovative platform, we will bring together a multidisciplinary consortium of academic and industry partners that combine their unique expertise in T cell therapy and immunology, synthetic biology, genome editing, cGMP manufacturing, bioinformatics, and communication. Easily integrable within CAR-T, TCR-T, and tumor-infiltrating lymphocyte (TIL) platforms, T-FITNESS will unleash the curative potential of T cell therapy for the benefit of an ever-growing number of cancer patients.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicineimmunology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesmedical biotechnologycells technologies
Parole chiave
Programma(i)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Argomento(i)
Invito a presentare proposte
HORIZON-EIC-2021-PATHFINDERCHALLENGES-01
Vedi altri progetti per questo bandoMeccanismo di finanziamento
HORIZON-EIC - HORIZON EIC GrantsCoordinatore
93053 Regensburg
Germania