This randomized phase II clinical trial evaluated the effectiveness of adding TLR agonists (poly-ICLC or resiquimod) to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant to enhance immune potency and safety. The combination of ATL-DC vaccination and TLR agonist was found to be safe and enhanced systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increased on CD4+ T-cells, while CD38 and CD39 expression were reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplified the induction of interferon-induced genes in monocytes and T lymphocytes. Patients with higher interferon response gene expression demonstrated prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population. The trial also reported long-term clinical outcomes, showing that patients treated with ATL-DC vaccination plus adjuvant TLR agonists had improved progression-free and overall survival compared to those treated with placebo. The interferon activation score in peripheral blood immune cells was a significant predictor of survival after ATL-DC therapy.This randomized phase II clinical trial evaluated the effectiveness of adding TLR agonists (poly-ICLC or resiquimod) to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant to enhance immune potency and safety. The combination of ATL-DC vaccination and TLR agonist was found to be safe and enhanced systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increased on CD4+ T-cells, while CD38 and CD39 expression were reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplified the induction of interferon-induced genes in monocytes and T lymphocytes. Patients with higher interferon response gene expression demonstrated prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population. The trial also reported long-term clinical outcomes, showing that patients treated with ATL-DC vaccination plus adjuvant TLR agonists had improved progression-free and overall survival compared to those treated with placebo. The interferon activation score in peripheral blood immune cells was a significant predictor of survival after ATL-DC therapy.