Making cold tumors hot: Multi-faceted Immunostimulatory Therapy for Ewing Sarcoma (MITES)
Ewing sarcoma (ES), the second most common bone cancer in children, remains a significant challenge in pediatric oncology. Survival rates for patients with recurrent or metastatic disease have not improved for decades, and no targeted treatments have succeeded for broad clinical use. Immunotherapy has revolutionized cancer treatment in recent years, but it has been poorly explored in the context of ES. Recent studies show that some ES patients exhibit high infiltration of cytotoxic immune cells, and that this is associated with greatly prolonged survival. Yet, the tumor-intrinsic factors that drive this favorable, “hot” immune phenotype spontaneously in some patients is a mystery. Children’ Hospital of Philadelphia’s research has identified such a factor, USP6, which has potent and pleiotropic immunostimulatory effects in jumpstarting the immune system, triggering infiltration of immune cells into the tumor, and stimulating their ability to kill the cancer cells. Concordantly, high USP6 levels are associated with dramatically improved survival in ES patients. These findings will be exploited to develop a novel immunotherapeutic agent to prevent ES recurrence and improve survival.
Defining the epigenetic and transcriptional signatures of chimeric antigen receptor T cell dysfunction
Chimeric antigen receptors (CARs) are engineered proteins that re-direct a patient’s immune system to target their cancer. T cells, the “killers” of the immune system, that are engineered to express CARs have demonstrated unprecedented results in the treatment of pediatric acute lymphoblastic leukemia, with ~9/10 patients becoming disease-free after treatment. Despite these exciting initial results, follow-up now shows that only half of patients treated will remain disease-free long-term. These clinical failures often result from failed T cell activity against leukemia cells. Washington University School of Medicine has recently identified that prolonged interaction between CAR T cells and leukemia cells can lead to T cell failure, however the biology responsible for this remains unclear. This research aims to identify the ways in which CARs promote T cell failure. Understanding this process will reveal strategies to engineer CAR T cells that are resistant to failure, resulting in more durable responses.