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

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 a-galactosylceramide (a-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 a-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 þ T-cell-mediated adaptive immune response. Pulsing a-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free a-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 agematched healthy volunteers. Furthermore, irradiated GBM tumor cells pulsed with a-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro.Conclusions: Injection of irradiated tumor cells loaded with a-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma.

CD4+ invariant natural killer T cells protect from murine GVHD lethality through expansion of donor CD4+CD25+FoxP3+ regulatory T cells

“…28,29 In humans, high iNKT cell numbers or activation of iNKT cells through glycolipids correlates with an improved outcome in different types of cancer. [30][31][32][33][34] Recent retrospective clinical data strongly support the beneficial immunologic effects of donor iNKT cells in the setting of allogeneic HCT in humans. Chaidos et al 35 showed in a multivariate analysis that a higher graft iNKT cell dose was associated with a significantly lower risk of acute GVHD.…”

Invariant NKT Cells Induce Plasmacytoid Dendritic Cell (DC) Cross-Talk with Conventional DCs for Efficient Memory CD8+ T Cell Induction

“…To maximally harness such immunological cascades, we established an efficient system using cells bearing a cell-associated Ag along with the iNKT cell ligand, a-galactosylceramide (a-GalCer). For example, we used iNKT ligand-loaded, tumor-associated Ag (TAA)-expressing CD1d + tumor cells (tumor/Gal) (19)(20)(21) or allogeneic fibroblasts loaded with a-GalCer transfected with TAA mRNA (16,22).…”

An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment

“…23,47,63 Although CD1d is weakly expressed on C1498 cells and has been identified in other acute leukemic cell lines, including AML-ETO9a, 23 EL4, and WEHI-3B (L.R.A, unpublished data, June 14, 2014), we have previously demonstrated that a CD1d-negative a-GalCer-pulsed glioma vaccine can provide protection against glioma challenge. 25 We have also shown that CD1d-deficient DCs can transfer a-GalCer to host resident CD1d-expressing antigenpresenting cells in vivo to induce potent invariant NKT-cell activation, which likely reflects transfer of a-GalCer embedded within membranes of the injected cells. 46 It is therefore not necessary for NKT cells to interact directly via CD1d on the cells of the vaccine to provide adjuvant activity.…”

“…21,22 The glycolipid a-galactosylceramide (a-GalCer) has recently been shown to be a useful adjuvant for whole tumor cell vaccination by eliciting stimulatory interactions between dendritic cells (DCs) and natural killer T (NKT) cells. [23][24][25][26] When DCs acquire cellular material from irradiated tumor cells that have been treated with a-GalCer, the protein content is presented as peptides via major histocompatibility complex (MHC) molecules to CD4 1 and CD8 1 T cells, whereas the a-GalCer is presented via the MHClike molecule CD1d to NKT cells. Interactions between DCs and NKT cells promote CD40 signaling, leading to DC activation, which increases the capacity of DCs to stimulate peptide-specific T cells.…”

“…23,24 Significantly, vaccines comprising irradiated tumor cells pulsed with a-GalCer have been shown to be effective in murine models of hematopoietic malignancies, including acute myeloid leukemia (AML) and acute lymphoid leukemia, 23,27,28 and in other malignancies. 25,27,29 Cancer-associated immunosuppression can present a significant barrier to effective vaccine-based immunotherapy. 30 AML generates an immunosuppressive environment, 31,32 characterized by impaired DC function 33 and increased levels of regulatory T cells (Tregs).…”