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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.

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.

Call for proposal

H2020-MSCA-IF-2020
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Funding Scheme

MSCA-IF-EF-CAR - CAR – Career Restart panel
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Coordinator

FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA
Address
Via Morego 30
16163 Genova
Italy
Activity type
Research Organisations
EU contribution
€ 171 473,28