Pre-doctoral Fellowship Grant Awarded to Prateek Thenge

This research project aims to develop a groundbreaking new treatment for diffuse intrinsic pontine glioma (DIPG),
a devastating brain cancer that primarily affects children. My approach combines two cutting-edge technologies:
gamma delta (γδ) T cells and advanced gene editing techniques. γδ T cells are unique immune cells that can
survive in harsh conditions and naturally detect and attack cancer cells. I plan to enhance the cancer-fighting
abilities of γδ T cells by equipping them with chimeric antigen receptors (CARs). These CARs act like a GPS,
guiding the γδ T cells to the vicinity of brain tumor cells, and once there, they function like a highly sensitive metal
detector, allowing the γδ T cells to detect and precisely target cancer cells for elimination. I’ll design two types of
CARs: one targeting a protein called B7H3 and another targeting HER2, both frequently found on DIPG tumor
cells. To further strengthen these modified γδ T cells, I’ll use CRISPR gene editing to remove genes that hold
back the T cell's ability to fight cancer and add new genes that help them stand up to the tumor’s defenses,
allowing the T cells to keep working effectively even when the tumor tries to shut them down. Additionally, I’ll test
a novel “dual-CAR” strategy, where cancer-detecting capability is split between two CARs on the same T cell. This
approach has shown promise in other immune cells because it makes it more difficult for the tumor cells to hide
and improves the durability of the T cells to increase effective tumor destruction. First, I’ll generate these
enhanced γδ T cells in the lab and test them against DIPG cells grown in culture dishes to select the top
performers. Next, I’ll evaluate these top performers in mouse models of DIPG, including models derived from
patient tumor samples. If successful, this project could lead to a powerful new immunotherapy for DIPG, offering
fewer side effects than current treatments. Moreover, the techniques developed through this research could
potentially be applied to other brain tumors and pediatric cancers. Ultimately, our group's goal is to generate
proof-of-concept data required to move this treatment into clinical trials, bringing new hope to children diagnosed
with DIPG and other difficult-to-treat brain cancers.