Co-Targeting Gangliosides to Overcome Antigen Heterogeneity in H3-Wildtype Pediatric High-Grade Glioma
Pediatric high-grade gliomas are among the deadliest childhood cancers. Survival has not improved in decades because these tumors grow quickly, resist standard treatments, and often return even after surgery, radiation, or chemotherapy. A small subset of these tumors carries an H3K27M mutation and shows high levels of a molecule called GD2 on the tumor surface. Early clinical trials using GD2-targeting CAR T cells, immune cells engineered to recognize GD2, have shown encouraging responses in these children. However, most high-grade gliomas do not carry this mutation. These “H3-wildtype” tumors are more variable in their biology and are not consistently treatable with GD2-CAR T cells because they show uneven (heterogeneous) expression of GD2. My early work shows that when GD2 is low, these tumors instead express high levels of GD3, a closely related molecule found on the tumor surface. This pattern suggests that many children who currently have no effective treatment might benefit from immunotherapy if we can target both molecules. Understanding how and why GD2 and GD3 appear on these tumors and how to safely target them is essential for expanding CAR T cell therapy to children who desperately need new options.
Project Goals
This project aims to develop a new immunotherapy for children with aggressive H3-wildtype high-grade gliomas who currently have no effective treatment options. My goal is to design CAR T cells, patient immune cells that are genetically modified to recognize cancer, that can target both GD2 and GD3, two related molecules found on these tumors. First, I will study how often GD2 and GD3 appear in H3-wildtype pediatric high-grade gliomas and confirm that they are not present on healthy tissues, an essential safety step. I will also analyze tumor samples to understand why some tumors express GD2, some express GD3, and how these patterns relate to the tumor’s underlying biology. Next, I will build and test bispecific CAR T cells that can recognize either GD2 or GD3. In early lab experiments, these dual-targeting cells successfully killed tumor cells expressing either molecule. I will now refine this CAR design and evaluate its safety and effectiveness in mouse models of pediatric glioma. By creating a therapy that targets both molecules at once, this work has the potential to prevent immune escape and offer a new treatment option for children with high-grade gliomas who currently have no curative therapies.
