Periodic Reporting for period 2 - EPI-CART (Understanding and exploiting epigenetic regulation in CAR T cell therapy)
Reporting period: 2023-06-01 to 2024-11-30
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.
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.
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.