Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma

Abstract

Background and objective: Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy).

Methods: Nine patients with newly diagnosed DIPG met enrollment criteria. Autologous dendritic cell vaccines (ADCV) were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received three boosts of tumor lysate every 3 months during the maintenance phase.

Results: Vaccine fabrication was feasible in all patients included in the study. Non-specific KLH (9/9 patients) and specific (8/9 patients) antitumor response was identified by immunologic studies in peripheral blood mononuclear cells (PBMC). Immunological responses were also confirmed in the T lymphocytes isolated from the cerebrospinal fluid (CSF) of two patients. Vaccine administration resulted safe in all patients treated with this schema.

Conclusion: These preliminary results demonstrate that ADCV preparation is feasible, safe, and generate a DIPG-specific immune response detected in PBMC and CSF. This strategy shows a promising backbone for future schemas of combination IT.

Keywords: cell; dendritic; diffuse intrinsic pontine glioma; immunotherapy; vaccination.

Figures

Figure 1

Therapeutic schema.

Figure 2

Consort diagram.

Figure 3

Characterization of dendritic cells (DCs) vaccines. (A) Increased expression of CD80, CD83, MHC class II, and CCR7 molecules on DCs surface membrane of autologous dendritic cell (ADC) compared to immature DC used as negative control. (B) Increased intensity of molecules (MFI) of ADC after stimulation compared to immature DC used as negative control.

Figure 4

Isolated and expanded T-cell obtained from CFS. (A) Antigen specificity of T cell from CSF was evaluated by cell proliferation (cpm indicates thymidine incorporation; cpm = counts per million) in response to KLH or tumor cell lines lysate. (B) T cell activation was measured by cytokine production (IFN-γ) in response to KLH or tumor cell lines lysate compared to negative.