Survival outcomes for patients with metastatic or relapsed sarcomas remain unacceptably low, with negligible progress observed over the past four decades, despite the application of intensive multimodal therapies. Fusion-driven sarcomas, including Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), are especially aggressive and predominantly affect children, adolescents, and young adults (AYA). Fusion genes, such as PAX3::FOXO1 in RMS and EWS::FLI1 in EWS, are causal for malignant transformation and tumor progression and therefore ideal targets for precision medicine but widely considered “undruggable” with convectional therapeutic approaches. 
We propose a fundamentally innovative strategy to therapeutically target sarcoma-driving fusions, utilizing the patient’s immune system. T cells can identify and eliminate malignant cells by recognizing cancer-associated alterations, e.g. fusion gene-derived (FGD) peptides. To train patients’ T cells to fight sarcoma, we have used a fusion gene-directed peptide vaccine in the PerVision study. Alternately, T cells can be engineered to target tumor cells. This strategy demonstrated promising clinical activity in other cancer entities. Within the TFUSION project, we will identify T cell receptors (TCRs) specifically targeting FGD peptides from vaccinated patients and healthy donors. TCRs will be engineered into T cells and functionally tested for specificity, safety, and anti-tumor activity. We will create libraries of functionally validated TCRs targeting FGD peptides, ready-to-use in TCR-engineered T cell (TCR-T) therapies. By focusing on recurrent fusion events, these TCRs will be amenable to treat broad EWS/RMS cohorts. 
Our proposed TCR-T therapies offer a highly specific, potent and potentially curative novel therapeutic approach, to be evaluated for safety and efficacy in a phase I/II clinical trial in advanced stage sarcoma patients.