Description du projet
Reprogrammer l’épuisement des lymphocytes T à l’aide de circuits logiques synthétiques
Les lymphocytes T font partie intégrante du système immunitaire. Ils reconnaissent et répondent à des portions spécifiques de particules étrangères ou de molécules cancéreuses modifiées. Ils éliminent directement les agents pathogènes et les cellules tumorales et envoient des messages au reste du système immunitaire pour renforcer sa réponse. L’exploitation de ces lymphocytes T dans les thérapies anticancéreuses s’est révélée d’une efficacité limitée dans le traitement des tumeurs solides, en grande partie en raison du phénomène d’épuisement des lymphocytes. Les lymphocytes T dits «épuisés» commencent à produire des quantités beaucoup plus faibles de protéines stimulant la réponse immunitaire et sont moins à même de tuer les cellules tumorales. Le projet T-FITNESS, financé par l’UE, développera une nouvelle approche pour rendre les lymphocytes T réfractaires à l’épuisement en utilisant des circuits logiques synthétiques fondés sur les microARN pour recâbler les réseaux transcriptionnels qui en sont responsables.
Objectif
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.
Champ scientifique
- 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
Mots‑clés
Programme(s)
- HORIZON.3.1 - The European Innovation Council (EIC) Main Programme
Thème(s)
Régime de financement
HORIZON-EIC - HORIZON EIC GrantsCoordinateur
93053 Regensburg
Allemagne