Description du projet
Améliorer la thérapie CAR T
Les lymphocytes T à récepteur antigénique chimérique (CAR) sont apparus comme un nouveau moyen de traiter le cancer, démontrant une efficacité remarquable contre certaines hémopathies malignes. Les données disponibles à ce jour attestent de leur efficacité limitée contre les tumeurs solides, principalement parce que les cellules CAR T tendent à s’épuiser et à perdre de leur efficacité dans le microenvironnement tumoral. Financé par le Conseil européen de l’innovation, le projet CAR T-REX entend contourner ce problème en introduisant un circuit génétique dans les cellules CAR T. Cela se fera par l’incorporation de miARN artificiels connus pour réguler à la baisse les gènes cibles responsables de l’épuisement. Le projet pourrait améliorer l’efficacité et la spécificité des immunothérapies cellulaires.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Régime de financement
HORIZON-EIC - HORIZON EIC GrantsCoordinateur
4805-017 Barco Gmr
Portugal
L’entreprise s’est définie comme une PME (petite et moyenne entreprise) au moment de la signature de la convention de subvention.