JOHN LEE, MD, PhD
David Geffen School of Medicine at UCLA
CureSearch Acceleration Initiative Award: 2023-2025
Focus: Ewing sarcoma
Project title: IL-18 armored STEAP1 CAR T cell therapy for Ewing sarcoma
"Metastatic Ewing sarcoma is rarely curable and current treatments like surgery, radiation and chemotherapy often don’t work well for advanced cases. Our hope is this treatment can one day lead to better outcomes for kids with this disease by making their immune systems better at fighting the cancer." - Dr. Lee
Ewing sarcoma (ES) is an aggressive and rare type of pediatric cancer involving bones and their surrounding soft tissue. In some cases, ES can become metastatic, meaning that it has spread to other parts of the body. Metastatic ES is a deadly disease, with a grim 5-year survival rate of 15-30%. Despite the availability of common treatments such as surgery, radiation, and chemotherapy, the prognosis of this disease remains poor. Therefore, new, and effective therapies are desperately needed for children with metastatic ES.
John Lee, MD, PhD is a CureSearch Acceleration Initiative Awardee at the David Geffen School of Medicine at the University of California, Los Angeles working on a new targeted immune-based treatment for advanced Ewing sarcoma. Dr. Lee has developed a chimeric antigen receptor (CAR) T cell therapy against a cell surface protein known as STEAP1. STEAP1, or six transmembrane epithelial antigen of the prostate 1, is present in >90% of ES tumors and is highly expressed on the surface of cancer cells, with limited expression in normal tissues. Additionally, it is implicated in cancer proliferation and invasion, making it an ideal candidate for immunotherapy in ES. Dr. Lee’s STEAP1 CAR T cells have shown promising initial results in ES models.
In his CureSearch-funded work, Dr. Lee proposes to further increase the cancer killing ability of STEAP1 CAR T cells by engineering them to secrete a molecule called interleukin-18 (IL-18). IL-18 is a proinflammatory cytokine that broadens anti-tumor immunity by enhancing the killing activity of CAR T cells and bridging the gap between innate and adaptive immune responses. By armoring STEAP1 CAR T cells with IL-18, Dr. Lee hopes to create a fourth generation of CAR T cells that overcome common barriers to utilizing CAR T cell therapy in solid tumors.
Dr. Lee will test the effectiveness and safety of his IL-18 armored STEAP1 CAR T cells in newly created models of ES that more closely resemble the advanced disease found in children. He hopes that these findings can be rapidly translated into a first-in-human clinical trial to evaluate this promising CAR T cell therapy in children with advanced ES, potentially bringing a new treatment option to the children who need it the most.