project . 2019 - 2024 . On going


Epigenetic fine-tuning of T cells for improved adoptive cell therapy
Open Access mandate for Publications
European Commission
Funder: European CommissionProject code: 803992 Call for proposal: ERC-2018-STG
Funded under: H2020 | ERC | ERC-STG Overall Budget: 1,489,720 EURFunder Contribution: 1,489,720 EUR
Status: On going
01 Jan 2019 (Started) 31 Dec 2024 (Ending)
Open Access mandate
Research data: No

Adoptive T cell therapy is a promising approach in various clinical settings, from target-specific immune reconstitution fighting cancer and chronic infections to combating undesired immune reactivity during auto-immunity and after organ transplantation. However, its clinical application is currently hampered by: 1) the acquisition of senescence during the required in vitro expansion phase of T cells which limits their survival and fitness after infusion into the patient, and 2) the functional plasticity of T cells, which is sensitive to the inflammatory environment they encounter after transfusion and which might result in a functional switch from the desired effect (e.g. immunosuppressive) to the opposite one (pro-inflammatory). I want to tackle these obstacles from a new molecular angle, utilizing the profound impact of epigenetic mechanisms on the senescence process as well as on the functional imprinting of T lymphocytes. Epigenetic players such as DNA methylation essentially contribute to T cell differentiation and harbor the unique prospect to imprint a stable developmental and functional state in the genomic structure of a cell, as we could recently show in our basic immune-epigenetic studies. Therefore, I here propose to equip T lymphocytes with the required properties for their successful and safe therapeutic application, including their functional fine-tuning according to the clinical need by directed modifications of the epigenome ('Epi-tuning'). To reach these goals I want: 1) to reveal strategies for the directed manipulation of the epigenetically-driven mechanism of cellular senescence and 2) to apply state-of-the-art CRISPR/Cas9-mediated epigenetic editing approaches for the imprinting of a desired functional state of therapeutic T cell products. These innovative epigenetic "one-shot" manipulations during the in vitro expansion phase should advance T cell therapy towards improved efficiency, stability as well as safety.

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