Project description
A ‘tweaking’ strategy for T lymphocytes according to the clinical needs
Adoptive T-cell therapy is a revolutionary approach in various clinical interventions, including target-specific cancer immunotherapy and fighting chronic infections, auto-immunity and undesired immune responses after organ transplantation. Currently, its clinical applications are complicated by the acquisition of senescence during the in vitro T-cell expansion phase, and by the functional plasticity of T cells which after transfusion may result in a functional switch from the desired effect. Epigenetic players such as DNA methylation contribute to T-cell differentiation, creating a unique possibility to stabilise the development and function of cells. The EU-funded EpiTune project aims to equip T lymphocytes with properties that would guarantee their successful and safe therapeutic application, including their functional fine-tuning according to the clinical needs. The idea is to improve T-cell therapy by directed modifications of the epigenome.
Objective
"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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Funding Scheme
ERC-STG - Starting GrantHost institution
10117 Berlin
Germany