TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial

• Published in: Nature communications 2024-05, Vol.15 (1), p.3882-13, Article 3882
• Main Authors: Everson, Richard G., Hugo, Willy, Sun, Lu, Antonios, Joseph, Lee, Alexander, Ding, Lizhong, Bu, Melissa, Khattab, Sara, Chavez, Carolina, Billingslea-Yoon, Emma, Salazar, Andres, Ellingson, Benjamin M., Cloughesy, Timothy F., Liau, Linda M., Prins, Robert M.
• Format: Article
• Language: English
• Subjects: 13/31; 38; 38/91; 59/57; 631/250/251; 692/4028/67/1922; Adult; Aged; Agonists; Biomarkers; Brain Neoplasms - drug therapy; Brain Neoplasms - immunology; Brain Neoplasms - therapy; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Carboxymethylcellulose Sodium - analogs & derivatives; CD38 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell activation; Clinical trials; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic structure; Effectiveness; Female; Gene expression; Glioma; Glioma - immunology; Glioma - therapy; Glioma cells; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; Imidazoles - therapeutic use; Immune system; Immunization; Immunotherapy; Immunotherapy - methods; Interferon; Interferons; Lymphocytes; Lymphocytes T; Male; Middle Aged; Monocytes; Monocytes - drug effects; Monocytes - immunology; multidisciplinary; Patients; PD-1 protein; Poly I-C - administration & dosage; Poly I-C - pharmacology; Polylysine - analogs & derivatives; Proteins; Science; Science (multidisciplinary); Toll-Like Receptor Agonists; Tumors; Vaccination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48073-y

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the 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 in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate 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.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684. Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.