Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy

Abstract

Purpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8-30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575-84. ©2017 AACR.

©2017 American Association for Cancer Research.

Figures

Figure 1. Progression-free and Overall Survival

Kaplan-Meier estimates of progression-free (A) and overall survival (B) in the intention-to-treat population. Vertical lines indicate time points at which patients were censored. Dotted-line curves indicate the 95% confidence interval.

Figure 2. Progression-free and Overall Survival by MGMT Methylation Status

Kaplan-Meier estimates of progression-free (panel A) and overall survival (panel B) in patients with available MGMT methylation status (n=42). Vertical lines indicate time points at which patients were censored.

Figure 3. Analysis of PD-L1 Expression on Myeloid Cells in Trial Patients

(A) Representative gating scheme for identification of myeloid cells from peripheral blood leukocytes by flow cytometry. Live cells were gated from the total population (left panel), followed by identification of single cells (center panel), and gating for total monocyte/myeloid population of CD45+/CD11b+ cells (right panel). (B) Representative analysis of PD-L1+ cells within the gated monocyte population. The cutoff for positive expression was defined by PD-L1 FMO (not shown) and confirmed by staining with PD-L1 isotype control (left panel). Positive cell populations were identified with PD-L1 staining in 32 patients, ranging from low expression (center panel) to high expression (right panel). (C) Summary of PD-L1 expression in monocytes from each of the 32 evaluated patients ordered by percent positive expression. Patients colored in gray (n=17) had expression equal to or less than the median (54.5% PD-L1+ monocytes) and were defined as low expressors. Patients colored in black (n=15) had expression above the median and were defined as high expressors.

Figure 4. Progression-free and Overall Survival by PD-L1 Expression

Kaplan-Meier estimates of progression-free (A) and overall survival (B) in the subgroup of patients with peripheral blood analysis divided by expression of PD-L1 on circulating monocytes (n=32). Vertical lines indicate time points at which patients were censored.