Biom-21. Molecular and Clinical Determinants of Response to Immunotherapy in High-Grade Glioma

While immunotherapy has transformed treatment in multiple solid tumors, its efficacy in high-grade glioma (HGG) remains limited. Understanding the molecular and clinical factors that influence HGG’s response to immunotherapy is essential to improving outcomes. We identified patients with grade 4 gliomas who had been treated with checkpoint inhibitor (CPI), virus therapy, or CMV-specific T- cell therapy and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes. We identified 66 patients, 57 glioblastoma and 9 astrocytoma, IDH-mutant grade 4; 38 were treated with CPI, 22 with virus therapy, and 6 with CMV-specific T- cell therapy. PIK3CA mutation was associated with shorter PFS and OS (p=0.022, 0.073, respectively) among all patients and a shorter OS among CPI-treated patients (p=0.004). PIK3CA wild-type tumors had less PD-1 expression in CD3+/CD8+ T cells. In CPI-treated patients, IDH1/2 mutation was associated with a shorter OS (p=0.002), and mutations in RB1 and TERT promoter were associated with a shorter PFS (p-value=0.00056, 0.022, respectively). Length of CPI therapy of more than 6 months was associated with increased PFS and OS (p=0.048, 0.062, respectively), while steroid use at baseline was associated with a shorter OS (p=0.00023). Multifocal disease was associated with shorter PFS and OS durations (p=0.0017, 0.0013, respectively) among all patients. In HGG, PIK3CA, IDH1/2, RB1, and TERT promoter mutations may be associated with a poor response to immunotherapy. These results need to be validated in larger studies. Our results may provide the rationale for clinical trials combining PI3K and IDH inhibitors with CPI in HGG.