Parra, Edwin Roger

Abstract 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.

Abstract Purpose While immunotherapy has transformed treatment in multiple solid tumors, its efficacy in high-grade glioma remains limited. Understanding the molecular and clinical factors that influence glioma’s response to immunotherapy is essential to improving outcomes. Methods We identified patients with recurrent glioblastoma or astrocytoma, IDH-mutant grade 4, who had been treated with checkpoint inhibitor (CPI), virus therapy, or cell therapy and determined the association between their molecular, clinical, and demographic characteristics and survival outcomes. Results 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 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). Tumor tissue without the mutation 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. Conclusions In high-grade glioma, PIK3CA, IDH1/2, RB1, and TERT promoter mutations may be associated with a poor response to immunotherapy. Our results may provide the rationale for clinical trials combining PI3K and IDH inhibitors with CPI in high-grade glioma.

Abstract Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. Patients and Methods: Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti–PD-1 response. Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). Conclusions: We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti–PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.