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CORDIS

A synthetic biology approach for T cell exhaustion

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.

Host institution

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Net EU contribution
€ 1 496 250,00
Address
VIA MOREGO 30
16163 Genova
Italy

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Region
Nord-Ovest Liguria Genova
Activity type
Research Organisations
Links
Total cost
€ 1 496 250,00

Beneficiaries (1)