Understanding and exploiting epigenetic regulation in CAR T cell therapy

Projektinformationen

EPI-CART

ID Finanzhilfevereinbarung: 101001971

DOI

10.3030/101001971

EK-Unterschriftsdatum 30 März 2021

Startdatum 1 Dezember 2021

Enddatum 30 November 2026

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 999 913,00

EU-Beitrag

€ 1 999 913,00

Koordiniert durch

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

Periodic Reporting for period 2 - EPI-CART (Understanding and exploiting epigenetic regulation in CAR T cell therapy)

Berichtszeitraum: 2023-06-01 bis 2024-11-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The dramatic efficacy of CAR T cell therapy in certain hematopoietic malignancies provides clinical validation of a groundbreaking paradigm: Human cells can be engineered into purpose-built therapeutic agents by genetically introducing artificial regulatory programs. The EPI-CART project focuses on epigenetic and transcriptional regulation in CAR T cell therapy – an important but underappreciated aspect of cell-based therapies.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

CRISPR-based functional genetic screens assess the impact of genetic modifications at the genome-wide level and could greatly accelerate the design of improved T cell-based therapies. We developed a novel technology to enable efficient genome editing and high-throughput screening in CAR T cells. The simultaneous delivery of the CAR and a CRISPR guide RNA enabled single-gene perturbation as well as genetic screens with libraries of target genes in CAR T cells directed against various antigens. Our mRNA-based protocol for the delivery of CRISPR modifiers extends the available tool kit for genome engineering in primary human T cells from loss-of-function mutations to precise base editing and CRISPR activation.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The EPI-CART project will advance our understanding of CAR T cell biology and establish new approaches for areas with unmet clinical need. We will establish preclinical proof-of-concept for the efficacy of CRISPR-boosted CAR T cells and provide a compelling rationale for subsequent first-in-human clinical trials. More generally, this project will demonstrate the biological roles and translational potential of epigenetic programs in cell-based therapy.