Targeting Ewing Sarcoma using a novel CAR T cell therapy
Ewing Sarcoma (ES) is the second most common and an aggressive bone cancer which occurs in children and young adults. While upfront therapy is effective for many patients with newly diagnosed localized ES, the prognosis remains extremely poor for patients with metastatic or recurrent ES. There have been no therapeutic advances for these patients for the past four decades, highlighting the critical need for novel approaches to metastatic and recurrent ES. Over the last decade immunotherapy has emerged as an effective treatment modality for a variety of cancers which are refractory to standard cytotoxic therapies. One such immunotherapy, Chimeric Antigen Receptor (CAR) expressing T cells, has demonstrated remarkable efficacy in the treatment of relapsed and refractory B cell malignancies in pediatric patients. Our choice to target CD99 antigen by immunotherapy in Ewing sarcoma was mainly driven by the elevated expression of CD99 on ES cells while its expression is much lower on the normal cells and blocking CD99 have previously been shown to substantially decrease ES tumor growth . Our newly engineered CD99 CAR-T cells demonstrated great efficacy against Ewing sarcoma. The main objective of our proposal is to evaluate the efficacy of CD99 CAR-T cells both to prevent and treat metastatic ES tumors. Further, we found that that low-dose radiation sensitizes Ewing sarcoma tumor cells to CD99 CAR-T cell tumor killing. Given these findings, we hypothesize that CD99 CAR-T cells will be effective against metastatic ES in a xenograft model and that the efficacy of the CAR-T cells can be further enhanced synergistically with radiation therapy. Through these studies, we will evaluate the potential of this novel immunotherapy as a new therapeutic strategy for metastatic ES, filling an unmet clinical need for improved therapies for patients with refractory or relapsed ES tumors.