John Lee, MD, PhD

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.

Research Update December 2024:

In the first 6 months of the award, Dr. Lee and his team have made considerable progress in investigating IL-18 armored STEAP1 CAR T cell therapy for safety and efficacy in preclinical studies. The team has completed experiments to show that their CAR T cell therapy demonstrates rapid and improved killing of Ewing sarcoma across multiple rechallenges over time. Additionally, they have obtained their first set of mice bearing human immune systems and have characterized these mice to ensure that they can appropriately support human immune cells. In upcoming experiments, the team will inject these mice with human Ewing sarcoma cells to determine how well tumors develop and spread. They will then use these new mouse models to test their IL-18 armored STEAP1 CAR T cells and determine barriers to effectiveness of this treatment. Additionally, Dr. Lee and his team have taken initial steps towards their goal of quickly moving this therapeutic approach to a first-in-human phase I clinical trial by the end of the award period, including working with companies to support the manufacturing of IL-18 armored STEAP1 CAR T cells for commercial use.