Abstract
Glioblastoma (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. Forty-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. Younger 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). For 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.
Highlights
Glioma is a commonly occurring form of brain tumor, and highgrade gliomas are the most common malignant tumors of the central nervous system [1, 2]
There was a total of 47 patients enrolled, of which 27 patients received autologous dendritic cell tumor antigen (ADCTA) added to conventional therapy (ADCTA group) and 20 patients received conventional therapy only
In this study of glioblastoma patients treated with adjuvant ADCTA immunotherapy compared to conventional adjuvant therapy, the treatment responsiveness in ADCTA group was found to be strongly associated with a low tumor infiltrating lymphocytes (TILs) PD-1+/CD8+ ratio within the glioblastoma tumor
Summary
Glioma is a commonly occurring form of brain tumor, and highgrade gliomas are the most common malignant tumors of the central nervous system [1, 2]. Glioblastoma multiforme (GBM) is the most lethal, with a mortality rate of 88% within 3 years [3]. GBM prognosis remains poor, with a median overall survival (OS) of 14.6 months for newly diagnosed GBM treated with temozolomide (TMZ) and a median OS of 7.4 months for recurrent GBM [4, 5]. Survival rates of patients with glioblastoma are relatively low, and the failure of treatments is mostly due to recurrence. GBM has a low survival rate attributed to unique treatment limitations such as a high cell proliferation, invasive infiltration, tumor location, and poor understanding of the tumor pathophysiology [11]. Glioblastoma (GBM) is the most common and lethal primary malignant glioma in adults. We retrospectively analyzed clinical and laboratory data to evaluate the factors affecting vaccine treatment
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