TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial
Year: 2024
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: Autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination is a promising immunotherapy for patients with high grade gliomas, but responses have not been demonstrated in all patients. To determine the most effective combination of autologous tumor lysate-pulsed DC vaccination, with or without the adjuvant toll-like receptor (TLR) agonists poly-ICLC or resiquimod, we conducted a Phase 2 clinical trial in 23 patients with newly diagnosed or recurrent WHO Grade III-IV malignant gliomas. We then performed deep, high-dimensional immune profiling of these patients to better understand how TLR agonists may influence the systemic immune responses induced by ATL-DC vaccination. Bulk RNAseq data demonstrated highly significant upregulation of type 1 and type 2 interferon gene expression selectively in patients who received adjuvant a TLR agonist together with ATL-DC. CyTOF analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased expression of PD-1 on CD4+ T-cells, decreases in CD38 and CD39 on CD8+ T cells and elevated proportion of monocytes after ATL-DC + TLR agonist administration. In addition, scRNA-seq demonstrated a higher expression fold change of IFN-induced genes with poly-ICLC treatment in both peripheral blood monocytes and T lymphocytes. Patients who had higher expression of interferon response genes lived significantly longer and had longer time to progression compared to those with lower expression. The results suggest that ATL-DC in conjunction with adjuvant poly-ICLC induces a polarized interferon response in circulating monocytes and specific activation of a CD8+ T cell population, which may represent an important blood biomarker for immunotherapy in this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01204684.
Source: Nature Communications
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1100959374, G3262768651, CNS Anti-tumor immunity induced by dendritic cell vaccination and TLR agonists, G562934659, Metastatic Clonal Heterogeneity and its Impact on Melanoma Therapeutic Resistance, Identification and cloning of neoantigen-specific T cells for GBM immunotherapy, Metabolic MRI for quantifying aerobic glycolysis and immune function in gliomas, G9000261587, Neoadjuvant checkpoint blockade for recurrent glioblastoma, UCLA SPORE in Brain Cancer, Quantitative molecular MR-PET imaging of glycolysis in glioblastoma, UCLA Tumor Immunology Institutional Training Grant, Cancer Center Support Grant, UCLA Clinical and Translational Science Institute, Role of decorin and diffusion MRI in anti-VEGF efficacy for recurrent glioblastoma
OpenAlex ID: W4396730983