Descripción del proyecto
Mejora del tratamiento de receptor quimérico para el antígeno
Los linfocitos T receptores de antígenos quiméricos (CAR) han surgido como una nueva forma de tratar el cáncer, al demostrar una eficacia significativa contra ciertas neoplasias malignas hematológicas. Hasta ahora, las pruebas demuestran su eficacia limitada contra los tumores sólidos, principalmente porque los linfocitos T-CAR tienden a agotarse y a ser menos eficaces en el microentorno tumoral. El objetivo del proyecto CAR T-REX, financiado por el Consejo Europeo de Innovación, es sortear este problema introduciendo un circuito genético en los linfocitos T-CAR. Esto se logrará mediante la incorporación de microARN artificiales conocidos por regular a la baja genes diana responsables del agotamiento. El proyecto puede mejorar la eficacia y especificidad de las inmunoterapias celulares.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Convocatoria de propuestas
HORIZON-EIC-2022-PATHFINDEROPEN-01
Consulte otros proyectos de esta convocatoriaRégimen de financiación
HORIZON-EIC - HORIZON EIC GrantsCoordinador
4805-017 Barco Gmr
Portugal
Organización definida por ella misma como pequeña y mediana empresa (pyme) en el momento de la firma del acuerdo de subvención.