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as loss of major histocompatibility complex (MHC) vaccination, given that these cells express increased levels
antigen expression that prevent their recognition by of MHCs and tumor associated antigens. This vaccination
the CD8 T cells. CD8 T cell cytotoxic activity has induced antigen-specific Th1 immune response and, when
+
[8]
+
been considered key for tumor eradication and these tested in 9 L CSCs brain tumor model, it resulted in robust
cells have been detected in GBM tissue. Furthermore, antitumor T-cell immunity and a significant survival
[16]
the tumor secretes factors that suppress T-cell benefit. Another interesting approach is the possibility
proliferation and dendritic cells maturation. Increased of preloading DC and CD14 cells with chemotherapeutic
+
ratio of CD3 and CD8 to FoxP3 T cell correlated drugs before immunotherapy. In a recent study, both CD14
+
+
+
significantly with patient’s survival in primary GBM. [9] and DCs were incubated with paclitaxel for 24 h. The cells
loaded the drug and this was subsequently released in the
Further suppression of the immune system in GBM conditioned medium. Growth inhibition was observed
patients can be caused by systematic corticosteroid when this medium was used to culture U87MG
treatment that is used for the reduction of vasogenic cells. Of note, U87MG is a commercial cell line
[17]
oedema and as a consequence of chemo-radiotherapy. that has been expanded in vitro for many passages,
The present review summarizes all major progresses thus its utility in defining therapeutic approaches
that have been made in immunotherapeutic for glioma is questionable.
treatments against gliomas, such as dendritic cells
based therapies, vaccines (such as EGFRvIII and VACCINES
IDH1), tumor specific targets, T cell engineering and
immune checkpoint inhibitors. The rational for vaccines lies in the presentation of
tumor associated antigens in the immune system.
DENDRITIC CELLS THERAPIES Several ways exist to provide antigens for vaccine
administration, one of which is autologous DC as
Dendritic cells (DC) are professional antigen previously described. Recently, a vaccine called
presenting cells (APC) and have been reported to Gliovac (ERC 1671), was prepared using autologous
be a promising treatment method against glioma. antigens that derived from excised tumor tissue
DCs can be subdivided into myeloid DC (mDCs) and were combined with allogeneic antigens from
and plasmacytoid DC (pDCs). Dendritic cells can be glioma tissue resected from other GBM patients.
extracted from blood and can be incubated with GBM This vaccine was capable of triggering powerful
cells. After antigen presentations, DC can be injected polyclonal immune reactions. When administered
back to patients as immunotherapy. However, this in 9 recurrent GBM patients, that were treated
approach requires firstly, tumor tissue collected with surgery, radiotherapy, temozolomide and
during surgery and secondly, several weeks for bevacizumab, the vaccine showed minimal toxicity
vaccination preparation. Side effects of this approach and enhanced overall survival that reached 77%
are minimal and several studies have shown that at 40 weeks. Vaccination with rindopepimut,
[18]
DCs are capable of inducing immune response. [10,11] composed of the EGFRvIII peptide sequence
[12]
Prins et al. compared the safety, feasibility, and conjugated to the immunogenic carrier protein
immune responses of malignant glioma patients that keyhole limpet hemocyanin, showed promise in a
were treated with DC pulsed with autologous tumor phase II study. The median progression-free survival
lysate or with synthetic glioma-associated antigens. and overall survival was 14.2 and 26 months in
The results showed that DCs pulsed with autologous vaccinated patients compared to 6.4 and 15.2 months
tumor lysates produced a better anti-tumor immune in controls, respectively. A Phase III clinical trial
[19]
response. When autologous DCs transfected with is now underway. One major disadvantage of peptide
[12]
autologous tumor stem cell-mRNA they induced an vaccines is that a different treatment strategy is
immune response against the patient’s GBM stem cells. The usually required when tumor recurs. Sampson et
vaccinated patients had significantly better progression- al. [20] showed that the EGFRvIII-targeted peptide
free survival. mDC proved to be superior to pDC in vaccine triggered loss of the EGFRvIII expression in
[13]
producing a robust antitumor T cell response resulting in 82% of patients at the time of tumor recurrence.
[14]
tumor eradication and better long-term survival in mice.
[15]
Recently, Mitchell et al. showed that pre-conditioning the The R132H mutation is a tumorigenic mutation and can
site of vaccination with a recall antigen such as tetanus/ be found in the majority of low grade gliomas, secondary
diphtheria toxoid can significantly increase the efficacy of GBMs and rarely on primary GBMs or gliosarcomas.
DC vaccination. Paradoxically, the presence of mutation is a favorable
prognostic marker, even when assessed in comparison
Apart from loading DC with regular antigens, Xu et al. used with the O6-methylguanine-DNA methyltransferase
[16]
cancer stem-like cells (CSC) as sources of antigens for DC promoter status. A vaccine of peptides encompassing
[21]

52 Neuroimmunol Neuroinflammation | Volume 3 | March 14, 2016