Descrizione del progetto
Migliorare la terapia a base di cellule T del recettore dell’antigene chimerico
I linfociti T del recettore dell’antigene chimerico (CAR, chimeric antigen receptor) si sono progressivamente affermati come un nuovo metodo per trattare il cancro, dimostrando un’efficacia significativa contro determinate neoplasie ematologiche. Ad oggi le evidenze dimostrano la loro bassa efficacia contro i tumori solidi, principalmente a causa del fatto che le cellule CAR T tendono ad esaurirsi e diventare meno efficaci nel microambiente tumorale. Finanziato dal Consiglio europeo per l’innovazione, il progetto CAR T-REX si propone di aggirare questo ostacolo introducendo un circuito genetico nelle cellule CAR T. A tal fine il progetto integrerà miRNA artificiali, noti per essere in grado di inibire i geni bersaglio responsabili dell’esaurimento delle cellule. CAR T-REX dispone delle potenzialità per migliorare l’efficacia e la specificità delle immunoterapie a base di cellule.
Obiettivo
Although immunotherapy of select hematological malignancies using Chimeric Antigen Receptor (CAR) redirected T lymphocytes has recently gained regulatory approval, successful treatment of solid tumors using CAR T cells remains elusive. One salient problem is the limited efficacy and untimely exhaustion of CAR T cells in the tumor microenvironment (TME).
Combining innovative methods of genome editing, chemistry and immunology, CAR T-REX proposes to explore a novel concept of building auto-regulated genetic circuits into CAR T cells to selectively circumvent their exhaustion upon activation in the TME. Genetic rewiring will be achieved by precisely inserting artificial miRNAs under endogenous exhaustion-related “Driver” promoters to downregulate “Target” genes that cause exhaustion. Proprietary technology enables specific replacement of the “Driver” gene without risking off-target mutations. Further advantages of combined insertion and silencing are (i) the ability to regulate when a gene is turned on/off by biologically and clinically relevant cellular cues, and (ii) multiple gene-knockdown with a single dsDNA cleavage and RNA-silencing of both alleles. These genetic modifications will be implemented using a novel high-performance peptide-based gene delivery platform with unlimited loading capacity, allowing combination of several types of cargo, as well as economical large scale GMP production. Rewired HER2/Neu (ErbB2) redirected CAR T cells will be tested on preclinical breast and gastric carcinomas, and variants that eliminate tumors resistant to conventional 2nd and 3rd generation peers (without adverse events) will be developed/manufactured following quality-by-design principles under GMP-like conditions, thus accelerating the pathway towards clinical translation. These approaches will also constitute a proof-of-concept for modifying therapeutic cell products, with the potential to considerably improve their safety, specificity, efficacy, scalability and cost.
Campo scientifico
Parole chiave
Programma(i)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Invito a presentare proposte
HORIZON-EIC-2022-PATHFINDEROPEN-01
Vedi altri progetti per questo bandoMeccanismo di finanziamento
HORIZON-EIC - HORIZON EIC GrantsCoordinatore
4805-017 Barco Gmr
Portogallo
L’organizzazione si è definita una PMI (piccola e media impresa) al momento della firma dell’accordo di sovvenzione.