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

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 alpha-galactosylceramide (alpha-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 alpha-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 alpha-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free alpha-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 alpha-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro. Conclusions: Injection of irradiated tumor cells loaded with alpha-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma. Clin Cancer Res; 18(23); 6446-59. (C) 2012 AACR.