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CORDIS

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.

Coordinator

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Net EU contribution
€ 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
€ 171 473,28