Project description
Improving CAR T therapy
Chimeric Antigen Receptor (CAR) T lymphocytes have emerged as a new way to treat cancer, demonstrating significant efficacy against certain haematological malignancies. Evidence so far demonstrates their limited effectiveness against solid tumours, mainly because CAR T-cells tend to become exhausted and less effective in the tumour microenvironment. Funded by the European Innovation Council, the CAR T-REX project aims to circumvent this issue by introducing a genetic circuit into CAR T-cells. This will be accomplished via the incorporation of artificial miRNAs known to downregulate target genes responsible for exhaustion. The project has the potential to improve the efficacy and specificity of cell-based immunotherapies.
Objective
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.
Fields of science
Keywords
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Funding Scheme
HORIZON-EIC - HORIZON EIC GrantsCoordinator
4805-017 Barco Gmr
Portugal
The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.