CTIM-18. DENDRITIC CELL VACCINATION IN CONJUNCTION WITH ADJUVANT TLR-3 AGONIST ADMINISTRATION ENHANCES PRO-INFLAMMATORY IMMUNE RESPONSES AND IS ASSOCIATED WITH EXTENDED SURVIVAL IN MALIGNANT GLIOMA PATIENTS

Abstract

Abstract Despite recent advances with immunotherapy in other tumor types, malignant glioma patients have not shown a therapeutic benefit, potentially due to the insufficient activation of an immune response. We and others have documented immune responses and extended survival following dendritic cell (DC) vaccination in small clinical trials. In this Phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant toll-like receptor (TLR) agonists. Treatment with TLRs in cancer patients has been shown to activate the innate immune response by inducing the expression of pro-inflammatory factors and cytokines. Twenty-three patients with WHO grade III or IV glioma received three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 in conjunction with either a placebo adjuvant, TLR-7 agonist (Resiquimod), or TLR-3 agonist (Poly ICLC). We observed a difference in survival for the DC-vaccinated patients who received adjuvant Poly ICLC treatment of 54 months over adjuvant placebo (20 months) and adjuvant Resiquimod (28 months) groups (P = 0.04). The patient cohorts were balanced for WHO grade, IDH mutation, and MGMT methylation status. Mass cytometry (CyTOF) analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of the monocyte populations CD14+CD16- and CD14dimCD16+ after Poly ICLC treatment. In addition, gene expression analysis of the PBMC populations using single cell RNA sequencing demonstrated increased expression of pro-inflammatory genes after adjuvant Poly ICLC and Resiquimod treatment. Nonetheless, a greater fold change increase and a larger pro-inflammatory repertoire was observed in the Poly ICLC group. Overall, these findings demonstrate that adjuvant Poly ICLC increases the number of circulating monocytes and induces a large pro-inflammatory response, which may account for the survival differences observed over adjuvant Resiquimod and placebo.