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A synthetic biology approach to engineering exhaustion-free T cell therapies. Uncovering and counteracting biomechanical triggers of T cell dysfunction in the tumour microenvironment.

Project description

Towards more sophisticated anti-cancer therapies

Chimeric antigen receptor (CAR) T cells have emerged as powerful anti-cancer weapons, demonstrating great clinical efficacy against haematological malignancies. However, prolonged antigen stimulation has hampered their effectiveness against solid tumours. The EU-funded Tex-Mex project will investigate the biomechanical triggers of the tumour microenvironment on prolonged T cell stimulation and dysfunction. Researchers will employ a microfluidic model that recapitulates all known parameters of T cell exhaustion and add a biomechanical dimension. Results will help address the bottleneck of CAR-T therapy associated with T cell exhaustion and advance it to a universal anti-cancer therapy.

Objective

Cancer is the second leading cause of death in the European Union, having killed 1.4 million people in 2018 alone. Chimeric antigen receptor (CAR) T cell therapy is a ground-breaking cancer treatment that has demonstrated striking results in fighting blood cancers. However, T cell exhaustion, a process that results in the progressive development of lymphocyte dysfunction due to prolonged antigen stimulation in cancer, chronic inflammation or infection, has been a major obstacle in translating CAR T cell therapy to solid tumours. The solid tumour microenvironment is biomechanically distinct from physiological conditions, being characterized by higher interstitial pressures, higher stiffness and a distinctive vascular architecture. While biochemical triggers for T cell exhaustion have been well characterized, biomechanical influences are understudied. This project seeks to (i) use a microfluidic model to add the biomechanical dimension to our current understanding of the development of T cell exhaustion and (ii) use synthetic biological approaches to engineer “biomechanosensor-actuator devices”. These will be intracellular systems based on synthetic biological circuits that will integrate biochemical and biomechanical cues of T cell exhaustion and trigger genetic pathways to counteract the development of dysfunctional phenotypes. Integrating the biomechanical and biochemical dimensions will yield a more sophisticated cell therapy platform to neutralize T cell exhaustion. Ultimately this would provide a safer, more effective and universal treatment for cancer by preventing T cell exhaustion and immune escape.

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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2020

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Coordinator

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 171 473,28
Address
VIA MOREGO 30
16163 Genova
Italy

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Region
Nord-Ovest Liguria Genova
Activity type
Research Organisations
Links
Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 171 473,28
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