Project description
Reprogramming T cell exhaustion using synthetic logic circuits
T cells are an integral part of the immune system, recognising and responding to specific portions of foreign particles or altered cancer molecules. They eliminate pathogens and tumour cells directly and send messages to the rest of the immune system to enhance its response. Harnessing these T cells in anti-cancer therapies has shown limited efficacy in treating solid tumours, largely due to so-called T cell exhaustion. ‘Exhausted’ T cells begin to produce much lower amounts of immune response-stimulating proteins and are less able to kill tumour cells. The EU-funded T-FITNESS project will develop a novel approach to make T cells refractory to exhaustion using microRNA-based synthetic logic circuits to rewire the transcriptional networks responsible for it.
Objective
Cell and gene therapies offer a massive paradigm shift from current treatment options and hold the potential to cure previously untreatable diseases. Naturally-occurring and genetically modified T cells with chimeric antigen (CAR) or T cell receptors (TCR) have demonstrated remarkable curative capacities against advanced hematologic malignancies but have shown limited efficacy in treating solid tumors. Major barriers hindering the full antitumor potential of T cells are the immunosuppressive signals and persisting antigenic stimuli within the tumor microenvironment that inexorably push T cells into a highly dysfunctional state called “exhaustion”. Herein, we propose a groundbreaking technology, T-FITNESS, which will enable antitumor T cells to become refractory to exhaustion. At the core of the platform are microRNA (miRNA)-based synthetic logic circuits capable of rewiring the transcriptional networks orchestrating T cell exhaustion. By harnessing the power of CRISPR/Cas genome editing, we will integrate sensors of miRNAs upregulated in exhausted cells into untranslated regions of one or more transcription factors driving T cell exhaustion, to enable their fine-tuned downregulation. We will validate the reprogramming efficacy of T-FITNESS by performing extensive functional analyses in vitro and in vivo and advance the best circuits towards the clinic by developing an automated cGMP-compliant manufacturing process for point-of-care production of T-FITNESS-edited CAR-T cells. To develop this innovative platform, we will bring together a multidisciplinary consortium of academic and industry partners that combine their unique expertise in T cell therapy and immunology, synthetic biology, genome editing, cGMP manufacturing, bioinformatics, and communication. Easily integrable within CAR-T, TCR-T, and tumor-infiltrating lymphocyte (TIL) platforms, T-FITNESS will unleash the curative potential of T cell therapy for the benefit of an ever-growing number of cancer patients.
Fields of science
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicineimmunology
- engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringsensors
- natural sciencesbiological sciencesgeneticsgenomes
- medical and health sciencesmedical biotechnologycells technologies
Keywords
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Topic(s)
Funding Scheme
HORIZON-EIC - HORIZON EIC GrantsCoordinator
93053 Regensburg
Germany