CAR T cells Rewired to prevent EXhaustion in the tumour microenvironment
CAR T-REX aims to enhance CAR T cell efficacy against solid tumors by integrating auto-regulated genetic circuits to prevent exhaustion, using advanced gene editing and delivery technologies.
Projectdetails
Introduction
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).
Project Overview
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
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.
Advantages of the Approach
Further advantages of combined insertion and silencing are:
- The ability to regulate when a gene is turned on/off by biologically and clinically relevant cellular cues.
- Multiple gene-knockdown with a single dsDNA cleavage and RNA-silencing of both alleles.
Gene Delivery Platform
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.
Preclinical Testing
Rewired HER2/Neu (ErbB2) redirected CAR T cells will be tested on preclinical breast and gastric carcinomas. 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.
Proof-of-Concept
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.
Financiële details & Tijdlijn
Financiële details
Subsidiebedrag | € 2.733.931 |
Totale projectbegroting | € 2.733.931 |
Tijdlijn
Startdatum | 1-4-2023 |
Einddatum | 30-6-2027 |
Subsidiejaar | 2023 |
Partners & Locaties
Projectpartners
- STEMMATTERS, BIOTECNOLOGIA E MEDICIINA REGENERATIVA SApenvoerder
- TARGETGENE BIOTECHNOLOGIES LTD
- UNIVERSIDAD DE SANTIAGO DE COMPOSTELA
- DEBRECENI EGYETEM
- STIFTUNG LEIBNIZ-INSTITUT FUR IMMUNTHERAPIE
- DEBRECENI EGYETEM
Land(en)
Vergelijkbare projecten binnen EIC Pathfinder
Project | Regeling | Bedrag | Jaar | Actie |
---|---|---|---|---|
FINE-TUNING T CELL NETWORKS OF EXHAUSTION BY SYNTHETIC SENSORST-FITNESS aims to enhance T cell therapy by preventing exhaustion through miRNA-based circuits and CRISPR/Cas editing, improving treatment efficacy for solid tumors in cancer patients. | EIC Pathfinder | € 4.387.825 | 2022 | Details |
Bottom-up manufacturing of artificial anti-tumor T cellsThe project aims to develop Artificial T cells (ArTCells) that mimic T cell therapy's anti-tumor functions more safely and cost-effectively, using engineered Giant Unilamellar Vesicles for targeted cancer treatment. | EIC Pathfinder | € 3.391.796 | 2024 | Details |
Hyper-targeting CAR NK cells from induced pluripotent stem cells for novel off-the-shelf anti-tumor therapiesThe HyperTargIPS-NK project aims to develop a scalable, off-the-shelf NK cell therapy using iPS cells to target and treat lethal cancers like pancreatic cancer, glioblastoma, and AML. | EIC Pathfinder | € 3.798.713 | 2023 | Details |
NOn-VIral gene modified STEM cell therapyThis project aims to develop a high-throughput protocol for producing gene-corrected CAR T cells and blood stem cells using optimized photoporation and CRISPR technology for enhanced clinical application. | EIC Pathfinder | € 3.644.418 | 2022 | Details |
Functional chemical reprogramming of cancer cells to induce antitumor immunityThe RESYNC consortium aims to revolutionize cancer immunotherapy by reprogramming cancer cells into antigen-presenting dendritic cells using small molecules for personalized and safer treatments. | EIC Pathfinder | € 2.966.695 | 2024 | Details |
FINE-TUNING T CELL NETWORKS OF EXHAUSTION BY SYNTHETIC SENSORS
T-FITNESS aims to enhance T cell therapy by preventing exhaustion through miRNA-based circuits and CRISPR/Cas editing, improving treatment efficacy for solid tumors in cancer patients.
Bottom-up manufacturing of artificial anti-tumor T cells
The project aims to develop Artificial T cells (ArTCells) that mimic T cell therapy's anti-tumor functions more safely and cost-effectively, using engineered Giant Unilamellar Vesicles for targeted cancer treatment.
Hyper-targeting CAR NK cells from induced pluripotent stem cells for novel off-the-shelf anti-tumor therapies
The HyperTargIPS-NK project aims to develop a scalable, off-the-shelf NK cell therapy using iPS cells to target and treat lethal cancers like pancreatic cancer, glioblastoma, and AML.
NOn-VIral gene modified STEM cell therapy
This project aims to develop a high-throughput protocol for producing gene-corrected CAR T cells and blood stem cells using optimized photoporation and CRISPR technology for enhanced clinical application.
Functional chemical reprogramming of cancer cells to induce antitumor immunity
The RESYNC consortium aims to revolutionize cancer immunotherapy by reprogramming cancer cells into antigen-presenting dendritic cells using small molecules for personalized and safer treatments.
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Chimeric Antigen Receptor (CAR) T Cell Therapy For Solid Tumors
CAR-T(uning) aims to enhance CAR-T therapy for NSCLC by improving treatment persistence and reducing tumor immunosuppression, paving the way for effective, broadly applicable cancer therapies.
Targeting of glycosylation pathways to empower CAR-T therapy of solid tumors.
This project aims to enhance CAR-T cell therapy for solid tumors by engineering glycosylation pathways to improve immune response and long-term persistence against immunosuppressive environments.
Engineering CAR-T cells to overcome glycosylation-driven tumour resistance
The project aims to engineer CAR-T cells that express an enzyme to de-glycosylate tumor cells, enhancing their efficacy against solid cancers by overcoming immunosuppressive barriers.
Synthetic Chimeric Antigen Receptors: Hijacking Nitrenium Ions for Targeting, Therapy and Safety of Next Generation T Cell Therapy
Develop a universal synthetic CAR T cell platform using activatable nitrenium ions to enhance targeting, control T cell function, and improve efficacy against solid tumors.
Polyclonal anti-tumor immunity by engineered human T cells
This project aims to enhance adoptive T cell therapies for solid tumors by engineering TCR sensitivity and safety, creating robust, antigen-agnostic immune responses to improve patient outcomes.