Synergistic treatment of solid tumours by engineering novel synthetic communication systems in T cells and Macrophages

Objective

In TeaM I propose a synthetic biology-based multi-cellular strategy to fight solid tumors, addressing the immunosuppressive tumour microenvironment (TME). WHY: Synthetic biology is transforming cell-based immunotherapies with control circuits in immune cells like T cells and macrophages. However, in solid tumours the TME renders these cells dysfunctional, limiting their efficacy. Innovative solutions are needed to address this unmet need and unlock the full potential of immunotherapies. WHAT: TeaM integrates synthetic biology, immunology, and artificial intelligence to arm CD8+T cells and macrophages with synthetic communication systems that sense the immunosuppressive TME and activate precise and localized therapeutic response. HOW: In the past years, also supported by an ERC Starting grant I made key contributions to mammalian cell engineering, addressing important bottlenecks with innovative solutions. Motivated by this progress, I am ready to challenge my know-how and investigate new frontiers in cell-based immunotherapies, driving revolutionary possibilities for cancer treatment. Leveraging my expertise in mammalian synthetic biology, we will design circuits that decode and reprogram the TME. Key innovations include: 1) Synthetic receptors targeting TME-specific molecules; (2) Humanized transcriptional activators; (3) Cell type-specific synthetic promoters devoid of off-target effects; (4) A Machine Learning model to optimize codon usage for balanced gene expression. These innovations will improve immune cell engineering for therapeutic interventions. IMPACT: TeaM will enable non-invasive real time characterization of TME dynamics under different therapeutic pressures improving our understanding of tumour responses, in preclinical studies. Moreover, it will be a breakthrough in cell therapies by coordinating therapeutic genes expression for TME reprograming and anti-cancer activity of engineered T cells and macrophages.