Projektbeschreibung
Erforschung der Epigenetik der CAR-T-Zelltherapie
Chimäre Antigenrezeptor-T-Zellen (CAR-T-Zellen) sind ein neuer Ansatz zur Stärkung des Immunsystems von Menschen in der Krebsbehandlung. CAR-T-Zellen sind patienteneigene Zellen, die so verändert werden, dass sie spezifische Antigene auf Krebszellen erkennen und diese zerstören. Im Rahmen des EU-finanzierten EPI-CART-Projekts soll unser Verständnis von CAR-T-Zellen aus epigenetischer Sicht verbessert werden, was bisher noch nicht untersucht wurde. Die Forschenden werden ein epigenetisches und transkriptomisches Profiling dieser Zellen nach einer Transplantation vornehmen. Die Verknüpfung dieser Informationen mit der Immunregulierung wird epigenetische Triebkräfte für die Reaktion der CAR-T-Zellen aufdecken und dazu beitragen, diese Immuntherapie für solide Tumoren zu optimieren.
Ziel
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.
Wissenschaftliches Gebiet
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Programm/Programme
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Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
1090 Wien
Österreich