Game Changer Grant Awarded to Pavithra Viswanath

Diffuse midline gliomas (DMGs) are devastating brain tumors in children. Immunotherapy using chimeric antigen receptor (CAR) T cells directed against the glycolipid GD2 has shown promise in the treatment of DMG patients. However, glioma-associated macrophages and microglia (GAMMs) infiltrate the tumor and suppress the tumor-killing capacity of CAR T cells. Our studies show that DMG cells upregulate an unusual metabolic enzyme called enolase 2 (ENO2) in GAMMs which then drives molecular alterations that block CAR T cell cytotoxicity. Importantly, treating mouse models of DMG with a safe, brain-penetrant ENO2 inhibitor reduces GAMM infiltration, restores the tumor-killing capacity of CAR T cells, and causes tumor shrinkage. Furthermore, we have developed an imaging agent that non-invasively monitors ENO2 activity in GAMMs and reports on tumor response to therapy. We anticipate that successful completion of our studies will lay the foundation for clinical translation of this novel immunometabolic therapy and imaging strategy to children with DMGs.