Understanding and exploiting epigenetic regulation in CAR T cell therapy

Informations projet

EPI-CART

N° de convention de subvention: 101001971

DOI

10.3030/101001971

Date de signature de la CE 30 Mars 2021

Date de début 1 Decembre 2021

Date de fin 30 Novembre 2026

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 999 913,00

Contribution de l’UE

€ 1 999 913,00

Coordonné par

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

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

Période du rapport: 2023-06-01 au 2024-11-30

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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.