Project description
Synthetic biology approach in T cell immunotherapy
Cell-based immunotherapies have enjoyed remarkable clinical success in recent years. However, long-term benefits are often compromised by dysfunction of T cells as a result of antigen chronic exposure, a process known as T cell exhaustion. Current treatments of T cell exhaustion are limited and demonstrate adverse effects. The EU-funded Synthetic T-rEX project aims to develop a strategy to reprogramme exhausted T-cells, using synthetic biology circuits. The project will construct specific, self-contained genetic circuits with improved parameters to minimise impact on normal cell physiology, targeting exhaustion-specific intracellular signals to rewire T cell activity and restore normal immune function. Genetic circuits will be developed based on identification of exhaustion-specific modifications from RNA and microRNA-sequencing profiles from ex vivo exhausted human CD8+ T cells.
Objective
Synthetic Biology has revolutionised approaches for several scientific, industrial and medical applications. These include the development of immunotherapies based on bioengineered cells, most notably engineering of patients T cells with tumor-targeting receptors, the CAR-T cells. Cell-based immunotherapies have shown remarkable clinical success; yet, long-term benefits are hampered by dysfunction of T cells occurring following antigen chronic exposure, a process known as T cell exhaustion. Current treatments of T cell exhaustion are limited and exhibit adverse effects.
Synthetic T-rEX aims to reprogram exhausted T-cells using synthetic biology circuits, to implement enhanced and more effective immune cell-based therapies. We will develop specific, self-contained genetic circuits with improved capabilities that minimise the impact on normal cell physiology; by pre-programmed integration of exhaustion-specific intracellular signals, these will rewire T cell activity and restore normal function. Circuits will be developed using a stepwise, bottom-up approach to identify exhaustion-specific inputs by RNA and microRNA-sequencing profile performed on ex vivo exhausted human CD8+ T cells. We will then design (a) synthetic promoters and (b) microRNA-regulated 5’UTR that will compute information processing to trigger output activation. Localised therapy will rely on concerted action of genetically encoded immune-checkpoint blockade and fine-tuning of epigenetic modulators that play a major role in T cell exhaustion. Finally, we will engineer T cells with sensor-actuator synthetic devices that revert exhaustion (T-rEX cells). In summary, our proposal provides a paradigm shift in the development of strategies against T cell exhaustion and a solid break-through towards enhanced natural and cell-based immunotherapy. More broadly, the proposed approach will unleash the potential of synthetic biology to the next level of therapeutic intervention.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- medical and health sciencesbasic medicinephysiology
- natural sciencesbiological sciencesgeneticsRNA
- medical and health sciencesbasic medicineimmunologyimmunotherapy
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Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
16163 Genova
Italy