Autologous tumor lysate-pulsed dendritic cell immunotherapy for pediatric patients with newly diagnosed or recurrent high-grade gliomas

Abstract

Immunotherapy has the potential to improve clinical outcomes with little toxicity for pediatric patients with brain tumors. We conducted a pilot feasibility study of tumor lysate-pulsed dendritic cell (DC) vaccination in pediatric patients (1 to 18 years old) with newly diagnosed or recurrent high-grade glioma (HGG). A total of nine DC vaccine doses, each containing 1 × 10(6) cells per dose were administered to three out of the seven originally enrolled patients. Toxicities were limited to mild side-effects, except in one case of elevated alkaline phosphatase, which resolved without clinical consequences. Two patients with primary lesions amongst the three vaccinated were alive at the time of writing, both without evidence of disease. Pre- and post-vaccination tumor samples from a patient with an anaplastic oligoastrocytoma that recurred failed to demonstrate immune cell infiltration by immunohistochemistry. Peripheral cytokine levels were evaluated in one patient following DC vaccination and demonstrated some changes in relation to vaccination. DC vaccine is tolerable and feasible with some limitations for pediatric patients with HGG. Dendritic cell based immunotherapy may provide some clinical benefit in pediatric patients with glioma, especially for patients with minimal residual disease, but further investigation of this modality is required.

Keywords: Pediatric neuro-oncology; dendritic cell vaccine; high grade glioma; immunotherapy.

Figures

Figure 1

Schematic for phase I clinical trial: Autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy for pediatric malignant glioma.

Figure 2

Flow cytometry of autologous dendritic cell culture prior to tumor lysate pulse. We desired a ‘large cell’ population that was >50% human leukocyte antigen-DR positive and >50% cluster of differentiation 14 (CD14)-negative to meet lot release criteria for tumor lysate-pulsing and administration. FSC, Forward scatter; SSC, side scatter.

Figure 3

Control cytokine bead analysis (CBA) using random donor HLA-A*0201 positive peripheral blood mononuclear cells stimulated with the influenza M1 peptide showing robust stimulation of interferon-γ and tumor necrosis factor-alpha (TNF-α). IL: interleukin; IFN-γ: interferon-gamma.

Figure 4

Representative images of T1 post-gadolinium magnetic resonance (MR) images. A and B: Pre-DC vaccination images of recurrent GBM for patient 1. C and D: Post-DC vaccination images of recurrent GBM for patient 1. E and F: Images for patient 4 at initial scan (E) and 13 months later after surgery, radiotherapy, chemotherapy, and DC vaccine (F).

Figure 5

Cytokine bead array analysis of cytokine levels from patient 4. *Days of vaccination; #actual value was >5000 pg/ml (above upper limits of the standards for this cytokine). TNF-α=tumor necrosis factor-alpha; INF-γ=interferon-gamma; IL=interleukin.