Jianping Huang, M.D., Ph.D., an associate professor in the department of neurosurgery in the University of Florida College of Medicine and director of clinical laboratory operations for the UF Brain Tumor Immunotherapy Program, has been awarded a grant from the Live Like Bella® Pediatric Cancer Research Initiative to begin a phase I/II clinical trial for malignant pediatric gliomas using 8R-70CAR T cells.
Brain tumors are the leading cause of cancer-related deaths in children younger than 20 in the United States. Among them, high-grade gliomas such as glioblastoma and diffuse intrinsic pontine gliomas have few treatment options. Identifying tumor-specific antigens is a critical step for developing treatments that will benefit these patients.
Tumor-specific targeted therapies, such as CAR T-cell therapy, have shown promise in previous studies. This therapy engineers a patient’s immune cells to attack tumors. Previous research highlighted a protein called CD70 as a target for treatment because this protein is highly expressed on tumor cells.
Huang and her team were the first to carry out a comprehensive analysis of the clinical relevance of CD70 expression in pediatric gliomas. They found that CD70 gene expression in glioblastoma leads to tumor progression by increasing tumor migration, invasion and proliferation. It also promotes an immunosuppressive tumor microenvironment by attracting tumor-associated macrophages. Furthermore, CD70 expression was found in MGMT-unmethylated glioblastoma in adult samples, suggesting these tumors are associated with temozolomide resistance.
To tackle the obstacles of CAR T-cell therapy and enhance antitumor efficacy in solid tumors, Huang and her team have co-opted IL-8 release from tumors (a strategy called the tumor positioning system) to guide and improve T-cell trafficking of CD70-specific CAR T cells (8R-70CAR T cells). Preclinical results show that 8R-70CAR T cells induce a potent antitumor response in glioblastoma models without an adverse effect. This research led to a phase I trial for adult patients with primary glioblastoma that will be initiated in the first quarter of 2023.
The newly funded project will apply these principles to pediatric malignant gliomas, which also overexpress CD70. The team has hypothesized that, just as in adults, CD70 in pediatric tumors functions as an immunosuppressive ligand and promotes tumor progression. The study will further clarify the mechanisms of CD70-mediated immunosuppression and tumor progression in pediatric brain tumors. It will also advance the clinical application of 8R-70 CAR T cell therapy in pediatric patients with malignant gliomas and other CD70-expressing cancers, such as acute myeloid leukemia and osteosarcoma.
“Pediatric gliomas are a complex and devastating cancer,” said Huang, a member of the Cancer Center’s Cancer Therapeutics & Host Response research program. “Through this project, we hope to find new ways to treat and cure them. I am grateful for the opportunity to contribute to this important work through this grant and am excited to see the impact it will have on the medical community.”