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T lymphocytes (CTL) engineered to express tumor 2DS2 positive NK cell subsets displayed a functional
antigen-specific proteins. Such targets are the activation advantage and resulted in greater cytokine
EGFRvIII, human epidermal growth factor receptor 2, production, propensity for degranulation and greater
erythropoietin-producing hepatocellular carcinoma persistence in vivo compared with KIR2DS2 negative
A2 (EphA2) and the interleukin-13 receptor NK cells. In order to enhance the killing capability
[49]
alpha2 (IL13Rα2). Recently, it has been suggested of cytotoxic lymphocytes, another approach was based
that EGFRvIII-directed CAR T cells are able to on the modulation of microvilli and filopodia that
suppress tumors of EGFRvIII (+) GBM in xenogeneic are characteristic of glioma cells. These structures
subcutaneous and orthotopic models. The EphA2 physically prevent cytolytic lymphocytes from
[41]
has been found increased in the majority of GBM eliminating glioma cells. In particular, knocking-
specimens and cell lines and at very low levels in down Fascin-1, an important scaffolding protein that
[43]
the normal brain. Chow et al. developed EphA2- is involved in the microvilli and filopodia formation,
[42]
specific T cells that resulted in regression of glioma resulted in increased lymphocyte cytotoxicity and
xenografts and better survival. The IL13Rα2 is a cell inhibition of cell proliferation and invasion.
[50]
surface receptor which is not significantly expressed Recently, the intratumoral administration of an
in normal brain but over-expressed in a subset of oncolytic adenovirus, the AdCMVdelta24, led to an
high-grade gliomas. Similarly, in a trial evaluating increased number of Interferon gamma-producing
an engineered chimeric antigen receptor, autologous CD8 T cells and a decrease in the tumor-infiltrating
+
primary human CD8 cytotoxic T lymphocytes regulatory T cells in a mouse model. [51]
+
targeting IL13Rα2 were tested for the treatment of
recurrent GBM. The intracranial administration was Interestingly, it has been suggested that radiotherapy
safe and promising in a pilot study of 3 patients. [44] complement immunotherapies; in fact, irradiated
cancer cells release peptides that can activate DC.
IMMUNE CHECKPOINT INHIBITORS Furthermore, radiotherapy in combination with
immune checkpoint inhibitors such as (anti-CTLA-4
Immune checkpoint inhibitors against regulatory and/or anti-PD-L1) may stimulate CD8 T cell-
+
pathways in T cells provide a gateway to development mediated anti-tumor immunity. [52]
[45]
of new treatments for several cancer types. This has
been explored in several tumors, by testing antibodies CONCLUSION
to cytotoxic T lymphocyte antigen-4 (CTLA-4),
i.e. an important immunosuppressive receptor, GBM is an extremely heterogeneous tumor, comprised
[53]
inhibition of indoleamine 2,3-dioxygenase 1 (IDO) of both differentiated and stem cells. This is
and blocking antibodies targeting either the receptor also highlighted in the recent gene expression-
of the programmed death 1 (PD-1) checkpoint or its based molecular classification of GBM into four
major ligand. For instance, in a murine GL261 glioma subtypes, namely Proneural, Neural, Classical and
[3]
model, a long-term survival in at least 50% of treated Mesenchymal. Thus, a multifaceted approach
animals was achieved by combining radiotherapy combining several treatment strategies might be
with anti-CTLA-4 antibodies and anti-4-1BB, that eventually required to achieve better results. Recent
[46]
+
drives the proliferation of CD8 T cells. Moreover, data seem to suggest that immunotherapy constitutes
using a syngeneic intracranial mouse glioma model, a promising treatment strategy for malignant gliomas
Wainwright et al. reported that simultaneous despite several limitations such as the modest Class
[47]
blockage of CTLA-4, IDO and PD-L1 results in long I MHC expression and the absence of Class II MHC
term survival of all mice. expression in tumor cells. Further combinatorial
treatments that involve the current standard therapies
OTHER APPROACHES and immunotherapeutic approaches are under way
and hopefully they will lead to more promising results.
Another interesting approach is based on macrophages
which have the ability to cross the intact blood brain Financial support and sponsorship
[48]
barrier. Baek et al. showed that macrophages Nil.
loaded with gold nanoshells could infiltrated into
glioma spheroids and after near-infrared light laser Conflicts of interest
irradiation there was complete growth inhibition There are no conflicts of interest.
in an irradiance-dependent manner. Recently,
allogeneic natural killer (NK) cells against patient- REFERENCES
derived GBM in vitro and in vivo have been tested 1. Liu Y, Shete S, Etzel CJ, Scheurer M, Alexiou G, Armstrong G,
with promising results. Killer Ig-like receptor (KIR) Tsavachidis S, Liang FW, Gilbert M, Aldape K, Armstrong T, Houlston

54 Neuroimmunol Neuroinflammation | Volume 3 | March 14, 2016