Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme

Abstract

BackgroundGlioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. Dendritic cell (DC) vaccines have demonstrated promising results in GBM clinical trials. However, some patients do not respond well to DC therapy, with survival rates similar to those of conventional therapy. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment.MethodsForty-seven patients with de novo GBM were enrolled at China Medical University Hospital between 2005 and 2010 and divided into two subgroups. One subgroup of 27 patients received postsurgical adjuvant immunotherapy with autologous dendritic cell/tumor antigen vaccine (ADCTA) in conjunction with conventional treatment of concomitant chemoradiotherapy (CCRT) with temozolomide. The other 20 patients received only postsurgical conventional treatment without immunotherapy. Immunohistochemistry for CD45, CD4, CD8, programed death ligand 1 (PD-L1), and programed death 1 (PD-1) was performed on sections of surgical tumor specimens and peripheral blood mononuclear cells (PBMCs). Pearson’s correlation, Cox proportional hazard model, and Kaplan–Meier analyses were performed to examine the correlations between the prognostic factors and survival rates.ResultsYounger age (<57 years), gross total resection, and CCRT and PD-1+ lymphocyte counts were significant prognostic factors of overall survival (OS) and progression-free survival (PFS) in the ADCTA group. Sex, CD45+ lymphocyte count, CD4+ or CD8+ lymphocyte count, tumor PD-L1 expression, isocitrate dehydrogenase 1 mutation, and O6 methylguanine-DNA methyltransferase promoter methylation status were not significant factors in both groups. In the ADCTA group, patients with tumor-infiltrating lymphocytes (TILs) with a lower PD-1+/CD8+ ratio (≤0.21) had longer OS and PFS (median OS 60.97 months, P < 0.001 and PFS 11.2 months, P < 0.008) compared to those with higher PD-1+/CD8+ ratio (>0.21) (median OS 20.07 months, P < 0.001 and PFS 4.43 months, P < 0.008). Similar results were observed in patients’ PBMCs; lymphocyte counts with lower PD-1+/CD8+ ratio (≤0.197) had longer OS and PFS. There was a significant correlation of PD-1+/CD8+ ratio between TILs and PBMCs (Pearson’s correlation R2 = 0.6002, P < 0.001). By contrast, CD4−, CD8−, but PD-1+, CD45+ tumor-infiltrating lymphocytes have no impact on OS and PFS (P = 0.073 and P = 0.249, respectively).ConclusionFor patients receiving DC vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT.

The Prognostic and Therapeutic Value of PD-L1 in Glioma

“…Moreover, PD-L1 inhibits chemokine production (e.g., CCL2-5 and CXCL9-10) that is crucial for recruitment of CTL, preventing the influx of CTL into tumor microenvironment (Gajewski et al, 2013). The roles of PD-1/PD-L1 pathway in inducing CTL exhaustion and Treg augment in tumor microenvironment have been verified in various cancer models (Dong et al, 2017; Jan et al, 2018).…”

“…The increase of PD-L1 + TIM surrounding glioma cells is associated with strong immune inhibition (Liu et al, 2008; Mirghorbani et al, 2013; Hosseini et al, 2015). Jan et al (2018) found that lower PD-L1 level in glioma cells is associated with neither abating immune inhibition nor better prognosis of glioma, which is probably linked with elevated PD-L1 + TIM in glioma microenvironment.…”

Innate Immune Cells: A Potential and Promising Cell Population for Treating Osteosarcoma

“…It is widely accepted that PD-1 is an exhaustion marker for CTL (134), which is the main anti-tumor effector cell during checkpoint blockade therapy. A study aiming to find predictors of DC vaccine responses showed that glioblastoma patients with tumor-infiltrating lymphocytes (TILs) with a higher PD-1 + /CD8 + ratio had worse prognosis (135). These data indicated that DC vaccine-primed CD8 + T cells became exhausted via the PD-1-PD-L1 axis, which is one of the reasons that DC vaccines have showed unsatisfactory results in osteosarcoma patients.…”

Clinical implication of cellular vaccine in glioma: current advances and future prospects

“…Hsu and colleague revealed a statistically significant correlation between higher degrees of TCR repertoires and prolonged overall survival in autologous tumor lysate-pulsed DC vaccines-treated GBM patients [ 87 ]. In a prospective case control study that enrolled 47 GBM patients with DC vaccine adjuvant therapy, better outcomes were predicted with younger age and a lower programmed cell death protein 1 (PD-1) + /CD8 + ratio in TILs and PBMCs [ 90 ]. Further analysis of the immune system factors demonstrated that the patients with an immune system equipped with favorable pre-existing or post-vaccination anti-tumor capabilities, such as IFN γ secretion and CD8 + cells, are more likely to live longer [ 91 ].…”