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

Abstract

Ewing Sarcoma (ES) is the second most common bone and soft tissue sarcoma affecting children, adolescents, and young adults. Despite very intensive multimodal therapies, the current overall survival remains dismal, particularly in patients with metastatic or refractory disease. This highlights the urgent need for innovative therapeutic approaches. Adoptive 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 TAA, ii) the widespread expression of TAA in normal tissues, leading to on-target off-tumour toxicities iii) and the presence of an immunosuppressive tumour microenvironment (iTME) that reduces CAR-T cells expansion and persistence at tumour sites. Here, we show preliminary data from ES cell lines and primary samples aiming to identify specific ES-targets with limited expression in healthy tissues to try to generate an efficient and safe CAR-T cell approach for treating metastatic and refractory ES.