Ewing Sarcoma (ES) is the second most common bone and soft tissue sarcoma affecting children and young adults. The dismal long-term survival in patients with metastatic/refractory disease is driven by the limited response rates to current multimodal therapies and the lack of actionable targets. This highlights the urgent need for developing new therapeutic approaches. Immunotherapy with chimeric antigen receptor (CAR)T-cells directed against a tumour-associated antigen (TAA) is a promising therapy with a safe and efficient profile in B-cell malignancies. However, the development of efficient and safe CAR T-cells for the treatment of ES is still challenging due to i) the low abundance of specific and safe TAAs, ii) and the presence of an immunosuppressive tumour microenvironment (iTME) that compromises CAR T-cells function. Here, we show preliminary data of specific ES-targets with limited expression in healthy tissues, the optimization of in vitro and in vivo cytotoxicity models which mimic the ES-iTME, and the initial assessment of a CAR T cell construct that turns the iTME to an immunologically hot tumour by triggering endogenous T-cell responses that enable epitope spreading.

An innovative tailored CAR T cell-redirecting immunotherapy for the treatment of metastatic and refractory Ewing Sarcoma