Funding
GoE
Genome of Europe
Immunosep
Personalized immunotherapy in sepsis: a precision medicine based approach
Understanding and exploiting epigenetic regulation in CAR T cell therapy
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.
EpiTargetkids
Studying epigenetic heterogeneity and phenotypic plasticity of pediatric high-grade gliomas for the development of novel strategies in precision medicine
Brain Resilience
PROMISE: Personalized Therapy for Immune-linked Disorders
Dissecting Cell Type-specific Chromatin Dynamics Driven by Oncogenic JAK-STAT Signalling
HDACs as regulators of T cell-mediated immunity in health and disease
GlioAge: Decoding cellular senescence in glioblastoma
LiquidBiopsyKids: Validation of a liquid biopsy based molecular diagnostic toolkit for pediatric sarcomas
PREDICTOME: Precision medicine for breast cancer: multi-omics towards predicting complete remission and avoiding surgery
