Game Changer Grant Awarded to Krishna Bhat

About 50% of all brain tumors in children are gliomas. Pediatric gliomas especially diffuse intrinsic pontine gliomas (DIPG) are aggressive cancers that are difficult to treat because of the molecular heterogeneity, inability of small molecular compounds to penetrate the brain to control the tumor and more importantly the inability to achieve surgical resection. Pediatric gliomas including DIPG are heavily infiltrated with innate immune cells called macrophages, which are generally thought as tumor promoting cells. However, recent evidence, including data from our lab, shows that these cells can be exploited to control tumor growth through activating receptors that engulf cancer cells. We have discovered that a molecule called Triggering receptor expressed on myeloid cells-2 (TREM2) is an important regulator of cancer cell engulfment in adult glioblastoma (GBM). TREM2 is
frequently degraded by enzymes and therefore cannot function effectively when expressed in macrophages. To this end, recent studies have shown that TREM2 can be artificially stabilized using antibodies that bind to TREM2 and prevent its degradation and improve its activity. We currently have access to a brain penetrating version of the antibody (thus addressing concerns about blood brain barrier penetration) that can stabilize TREM2 and increase in tumor engulfment leading to inhibition of tumor growth, but this has not been tested in pre-clinical models of DIPG. TREM2 based antibodies have reached human clinical trials offering an unprecedented opportunity to target DIPG using similar approaches. With funding from the ChadTough Defeat DIPG Foundation, we hope to accelerate this novel mode of immunotherapy treatment into clinical trials for DIPG patients.