Description du projet
Plonger dans l’épigénétique de la thérapie cellulaire CAR-T
Les cellules T des récepteurs antigéniques chimériques (CAR-T) constituent une nouvelle approche pour renforcer le système immunitaire d’un patient dans la lutte contre le cancer. Les CAR-T sont des cellules de patients conçues pour détecter des antigènes spécifiques sur les cellules cancéreuses et les détruire. La portée du projet EPI-CART, financé par l’UE, est d’accroître notre compréhension des CAR-T d’un point de vue épigénétique, quelque chose qui n’a jamais été étudié auparavant. Les chercheurs entreprendront le profilage épigénétique et transcriptomique de ces cellules après la transplantation. Lier ces informations à la régulation immunitaire découvrira les moteurs épigénétiques de la réponse des cellules CAR-T et contribuera à optimiser cette immunothérapie pour les tumeurs solides.
Objectif
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 will focus on epigenetic regulation in CAR T cell therapy – an important but underappreciated aspect of all cell-based therapies.
We will investigate the regulatory dynamics during CAR T cell therapy in unprecedented molecular detail, by following 40 patients who will receive treatment for two blood cancers (Aim 1). Using single-cell epigenome/transcriptome profiling of CAR T cells and sequential biopsies, clonal tracking, monitoring of immune regulation, and liquid biopsies, we will bioinformatically reconstruct patient-specific trajectories, identify molecular markers for therapy monitoring, and uncover epigenetic drivers of CAR T cell response.
To engineer the first “epigenetically boosted” CAR T cells for hard-to-treat cancers (CAR-T-resistant blood cancers, solid tumors), we developed a CAR T cell screening/engineering platform that enables us to functionally test thousands of potential regulators in cellular assays and mouse tumor models (Aim 2). The in vivo experiments leverage our CRISPR single-cell sequencing method (CROP-seq), supporting rational optimization of CAR T cells and quantitative modeling of the underlying regulatory mechanisms.
The EPI-CART project will uncover key roles of epigenetic regulation in CAR T cells, advance our understanding of existing CAR T cell therapies, and establish new approaches for areas with unmet clinical need. We will establish preclinical proof-of-concept for the efficacy of “epigenetically 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.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
1090 Wien
Autriche