CAR T cells Rewired to prevent EXhaustion in the tumour microenvironmentbroad
CAR T-REX · Horizon Europe grant · 2023-04-01–2027-06-30
EC contribution
Total cost
Beneficiaries
About the data
Source: CORDIS (official EU open data), Horizon Europe. Framework HORIZON · call HORIZON-EIC-2022-PATHFINDEROPEN-01 · scheme HORIZON-EIC · topic HORIZON-EIC-2022-PATHFINDEROPEN-01-01. CORDIS record →
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.
Beneficiaries (5)
| Organisation | Country | Role | EC contribution | SME |
|---|---|---|---|---|
| STEMMATTERS, BIOTECNOLOGIA E MEDICIINA REGENERATIVA SA | PT | coordinator | €783,240 | Yes |
| TARGETGENE BIOTECHNOLOGIES LTD | IL | participant | €855,506 | Yes |
| UNIVERSIDAD DE SANTIAGO DE COMPOSTELA | ES | participant | €560,512 | |
| STIFTUNG LEIBNIZ-INSTITUT FUR IMMUNTHERAPIE | DE | participant | €534,672 | |
| DEBRECENI EGYETEM | HU | participant | €0 |
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