Induction of CD8⁺T-Cell Responses Against Novel Glioma–Associated Antigen Peptides and Clinical Activity by Vaccinations With α-Type 1 Polarized Dendritic Cells and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Patients With Recurrent Malignant Glioma

TLDR

A phase I/II trial evaluated the safety and immunogenicity of α‑type 1 polarized dendritic cell vaccines loaded with synthetic peptides targeting glioma‑associated antigens (EphA2, IL‑13Rα2, YKL‑40, gp100) combined with poly‑ICLC in HLA‑A2+ patients with recurrent malignant glioma, administering 1–3×10^7 cells intranodally every two weeks and poly‑ICLC intramuscularly twice weekly, with booster doses for responders. The vaccine regimen was well tolerated, induced antigen‑specific immune responses in 58% of patients, upregulated type‑1 cytokines and chemokines, and produced clinical benefit with nine patients achieving ≥12 months progression‑free survival, one patient attaining a sustained complete response, and IL‑12 production by αDC1 correlating with longer progression‑free intervals, supporting its safety, immunogenicity, and preliminary activity.

Abstract

A phase I/II trial was performed to evaluate the safety and immunogenicity of a novel vaccination with α-type 1 polarized dendritic cells (αDC1) loaded with synthetic peptides for glioma-associated antigen (GAA) epitopes and administration of polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in HLA-A2(+) patients with recurrent malignant gliomas. GAAs for these peptides are EphA2, interleukin (IL)-13 receptor-α2, YKL-40, and gp100.Twenty-two patients (13 with glioblastoma multiforme [GBM], five with anaplastic astrocytoma [AA], three with anaplastic oligodendroglioma [AO], and one with anaplastic oligoastrocytoma [AOA]) received at least one vaccination, and 19 patients received at least four vaccinations at two αDC1 dose levels (1 × or 3 × 10(7)/dose) at 2-week intervals intranodally. Patients also received twice weekly intramuscular injections of 20 μg/kg poly-ICLC. Patients who demonstrated positive radiologic response or stable disease without major adverse events were allowed to receive booster vaccines. T-lymphocyte responses against GAA epitopes were assessed by enzyme-linked immunosorbent spot and HLA-tetramer assays.The regimen was well-tolerated. The first four vaccines induced positive immune responses against at least one of the vaccination-targeted GAAs in peripheral blood mononuclear cells in 58% of patients. Peripheral blood samples demonstrated significant upregulation of type 1 cytokines and chemokines, including interferon-α and CXCL10. Nine (four GBM, two AA, two AO, and one AOA) achieved progression-free status lasting at least 12 months. One patient with recurrent GBM demonstrated sustained complete response. IL-12 production levels by αDC1 positively correlated with time to progression.These data support safety, immunogenicity, and preliminary clinical activity of poly-ICLC-boosted αDC1-based vaccines.