MODL-34. A SERIES OF EGFR-MUTANT MODELS OF GLIOBLASTOMA THAT RECAPITULATES PATIENT TUMOR HETEROGENEITY AND RESPONSE TO TREATMENT

Abstract

Abstract Glioblastoma (GBM) is the most common and aggressive brain cancer, with a treatment regimen that has remained disappointingly unaltered for the last few decades. Preclinical testing of immunotherapy has generated promising results, sometimes leading to elimination of the tumor over time in mouse models; however, when tested clinically, patients show limited responses with no impact on patient survival. Current mouse models (e.g., GL261) for preclinical testing involve orthotopic transplantation of a cell line with tumor mutations not commonly found in patient tumors. Most of these models elicit a strong anti-tumor immune response which is typically not found clinically. Single cell sequencing has revealed that different mutations in GBM are associated with differences in the aggressiveness and composition of the tumor immune microenvironment. We therefore developed an immunocompetent, autochthonous platform for generating mouse models of GBM using combinations of clinically-relevant mutations, including mutant EGFR driving tumor growth and various single guide RNAs with CRISPR-Cas9 to elicit loss of function of tumor suppressor genes. Histopathology from tumors in mice mirrors the typical features of GBM, while single-cell RNA sequencing identified expression patterns similar to patients with different driver combinations altering expression patterns in ways that mimic their human counterparts, including the heterogeneity that is the hallmark of GBM. The immune cell population of these tumors was composed of predominantly microglia, with a small population of peripherally derived immune cells. Finally, treatment studies of radiation and anti-PD-1 using this new mouse model do not result in long-term survival, similar to human trials of these agents, paving the way for more accurate preclinical testing. In conclusion, using this unique modeling system that more closely resembles human tumors genetically and immunologically, we can better explore the mechanisms of therapeutic resistance and identify more relevant targets to improve outcomes in this challenging disease.