Descrizione del progetto
Approfondire l’epigenetica della terapia a base di cellule T del recettore dell’antigene chimerico
Le cellule T del recettore dell’antigene chimerico (CAR T, chimeric antigen receptor T cell) costituiscono un nuovo approccio per potenziare il sistema immunitario di un paziente nella lotta contro il cancro. Le CAR T sono cellule del paziente ingegnerizzate per rilevare particolari antigeni nelle cellule tumorali e distruggerle. L’obiettivo del progetto EPI-CART, finanziato dall’UE, è migliorare la nostra comprensione delle CAR T da un punto di vista epigenetico, un aspetto mai approfondito prima d’ora. I ricercatori tracceranno profili epigenetici e trascrittomici di queste cellule dopo il trapianto. Il collegamento tra queste informazioni e la regolazione immunitaria svelerà i fattori epigenetici della risposta delle cellule CAR T e contribuirà all’ottimizzazione di questa immunoterapia per i tumori solidi.
Obiettivo
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.
Campo scientifico
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Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
1090 Wien
Austria