Devising Advanced TCR-T cells to eradicate OsteoSarcoma

Osteosarcoma is the most common bone cancer in children and adolescents, affecting approximately 1,100 young patients in the European Union each year. In contrast to other pediatric cancers, the clinical treatment of osteosarcoma, which relies on high- dose chemotherapy and radical surgery, has not improved in over 40 years and nearly 30% of young patients still die from this devastating disease. DART2OS aims to break this stalemate by developing a new type of personalized immunotherapy that exploits an unusual feature of osteosarcoma. While most childhood cancers harbor relatively few genetic mutations, the chromosomes of osteosarcoma cells are typically broken and reshuffled in very complex ways. This has complicated the search for new therapies, but also comes with an opportunity: the reshuffling of chromosomes leads to the formation of altered proteins that do not occur in normal cells and thus can be detected by our immune system. Specifically, T-cells can recognize pieces of such altered proteins on the surface of cancer cells and then kill cancer cells very effectively. However, due to the chromosome reshuffling, each patient harbors different mutations and altered proteins, so T-cell-based immunotherapies will require the engineering of specific T-cells for each individual patient. To achieve this, DART2OS will combine cutting-edge research technologies in a highly collaborative research effort to establish a clinically applicable workflow for the engineering of fully personalized T-cell receptor transgenic T-cells. Specifically, the DART2OS team will: (1) Combine state-of-the-art single-cell sequencing and imaging technologies, computational approaches, and fully personalized genetic screens to identify T-cell receptors that can recognize osteosarcoma cells. (2) Apply innovative genetic engineering and molecular imaging approaches to further boost the anti-tumor activity of engineered T-cells. (3) Investigate the mechanisms by which osteosarcoma cells can escape T-cell attack and use this knowledge to develop therapeutic strategies to overcome such immune evasion. To accomplish these ambitious goals, DART2OS will bring together a team of experts in clinical diagnostics, cancer biology, immunology, biotechnology, and bioinformatics who will closely collaborate with leading research institutions and clinical centers to facilitate the translation of personalized therapies into clinical practice. DART2OS aims to pave the way for personalized T-cell-based immunotherapies that could transform the treatment of pediatric osteosarcoma and serve as a blueprint for the development of personalized immunotherapies in other pediatric and adult cancers.