Description du projet
La thérapie cellulaire ciblant la vasculature tumorale
L’approche visant à cibler la vasculature tumorale constitue depuis peu une stratégie de traitement anticancéreuse prometteuse. L’objectif du projet AngioCAR, financé par l’UE, est de développer une thérapie cellulaire adoptive basée sur les lymphocytes T à récepteur antigène chimérique (CAR) dirigés contre les nouveaux vaisseaux se formant dans des tumeurs solides. Les lymphocytes T CAR porteront des anticorps contre une forme extracellulaire de la vimentine, une protéine cytosquelettique que l’on retrouve spécifiquement dans les tumeurs. Les lymphocytes T CAR ciblant la vimentine faciliteront l’éradication de cellules endothéliales et auront également pour effet d’augmenter l’inflammation locale, réduisant ainsi l’immunosuppression. L’approche AngioCAR, utilisée seule ou en association avec des inhibiteurs de points de contrôle immunitaire, ouvrira de nouvelles possibilités pour la mise en place d’une thérapie efficace contre le cancer.
Objectif
Advances of adoptive cellular therapy and monoclonal antibodies (mAbs) have resulted in unprecedented responses in patients with malignant tumors. Due to the fact that tumor growth and metastasis depend on the formation of new blood vessels, termed angiogenesis, direct targeting of the tumor vasculature provides a universal point of engagement in the battle against cancer. The main objective of this project is the development of chimeric antigen receptor (CAR) T cell approaches to target the tumor vasculature. Although extremely effective in hematological malignancies, success of CAR T cell strategies against solid tumors is lagging behind. It is hypothesized that aiming CAR T cells towards the tumor vasculature will be effective, as (i) the target is readily accessible via the blood stream and (ii) the engineered T cells do not need to enter the immunosuppressive environment of the tumor. Vimentin, which is known as a cytoskeletal protein, was found to massively externalize from tumor endothelial cells and to become deposited in the surrounding matrix, while expression in all other cells is exclusively intracellular. Therapeutic targeting of this extracellular vimentin (eVim) with antibodies – or through vaccination – resulted in pronounced inhibition of tumor growth, in absence of toxicity. AngioCAR is a multidisciplinary project, aimed to develop CAR T cells against eVim for targeting of solid tumors. Newly developed antibodies against eVim will be expressed as the CAR to redirect T cells to the tumor vasculature. This will not only result in direct endothelial cell killing, but will also increase local inflammation and reduce immune suppression. The project also aims for testing the possible synergistic combination with checkpoint inhibitors as well. AngioCAR results have the potential capacity to open new avenues in cancer treatment in terms of enhancing specificity and efficiency.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
1081 HV Amsterdam
Pays-Bas