Vaccination With Irradiated Tumor Cells Pulsed With an Adjuvant That Stimulates NKT Cells Is an Effective Treatment for Glioma

Clin Cancer Res. 2012 Dec 1;18(23):6446-59. doi: 10.1158/1078-0432.CCR-12-0704. Epub 2012 Nov 12.

Abstract

Purpose: The prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor despite recent treatment advances. There is an urgent need to develop novel therapies for this disease.

Experimental design: We used the implantable GL261 murine glioma model to investigate the therapeutic potential of a vaccine consisting of intravenous injection of irradiated whole tumor cells pulsed with the immuno-adjuvant α-galactosylceramide (α-GalCer).

Results: Vaccine treatment alone was highly effective in a prophylactic setting. In a more stringent therapeutic setting, administration of one dose of vaccine combined with depletion of regulatory T cells (Treg) resulted in 43% long-term survival and the disappearance of mass lesions detected by MRI. Mechanistically, the α-GalCer component was shown to act by stimulating "invariant" natural killer-like T cells (iNKT cells) in a CD1d-restricted manner, which in turn supported the development of a CD4(+) T-cell-mediated adaptive immune response. Pulsing α-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free α-GalCer. To investigate the potential for clinical application of this vaccine, the number and function of iNKT cells was assessed in patients with GBM and shown to be similar to age-matched healthy volunteers. Furthermore, irradiated GBM tumor cells pulsed with α-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro.

Conclusions: Injection of irradiated tumor cells loaded with α-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / metabolism
  • Animals
  • Brain Neoplasms / immunology*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / therapy
  • CD4-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glioma / immunology*
  • Glioma / mortality
  • Glioma / therapy
  • Humans
  • Lung / immunology
  • Lymph Nodes / immunology
  • Lymphocyte Activation
  • Lymphocyte Depletion
  • Mice
  • Mice, Knockout
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Burden / immunology

Substances

  • Adjuvants, Immunologic
  • Cancer Vaccines