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Sager et al. Neuroimmunol Neuroinflammation 2018;5:25 I http://dx.doi.org/10.20517/2347-8659.2018.12 Page 5 of 11

Approaches for modulation of DC migration may prove to be a viable treatment option, however, modification
of autologous DCs is a difficult task with a high cost and workload.

Another appealing immunotherapy approach includes targeting of the glioma stem cells (GSCs) which are
considered to take part in treatment resistance [30,66] . A survival benefit has been achieved in rodent GB
models by use of GSC-antigens loaded DC vaccination [30,67,68] .

Heat shock protein vaccines
Targeting of a single TSA or TAA with vaccines limit the potential antitumoral effect to the subgroup of
GB patients expressing those TSAs and TAAs. Single-antigen vaccines also suffer from the heterogeneity
of the GB cells expressing the antigen which may lead to their diminished activity and usefulness. In this
context, an alternative strategy has been developed including vaccination with a heat shock protein (HSP)
peptide complex in order to achieve targeting of multiple antigens . The concentrations of HSPs may
[69]
reach high levels in the presence of protein misfolding, unfolding, or aggregation and under stress-inducing
environments as in GB [69-72] .

The use of HSP-peptide complex in management of recurrent GB patients has been tolerated well and
conferred an improvement of survival through enhanced immune response .
[73]

In a study by Crane et al. , the use of peptides bound to a 96 kD chaperone protein (HSP-96) for immunization
[74]
of recurrent GB patients resulted in a median survival of 47 weeks after surgery and vaccination, indicating
the efficacy of this approach. Another phase II trial by Bloch et al. reported the safety of HSPPC-96 vaccine
[75]
in 41 recurrent GB patients and emphasized the need for vigilance for pretreatment lymphopenia as a factor
impacting outcomes of immunotherapy.

The utility of another glioma-associated antigen HSP47 was suggested to induce CTL responses with the
potential of therapeutic exploitation for GB patients [76,77] .

Immune checkpoint therapy
Immune checpoint inhibitors are immunomodulatory therapeutics with the capability of blocking
inhibitory molecules and their receptors on effector immune cells with a resultant T-cell response against
various cancers . Immune checkpoint therapy offers a viable immunotherapy strategy targeting the
[78]
regulatory pathways in T cells to evoke an immune response against the tumor . Boosting of the antitumor
[79]
immunity by immune checkpoint inhibitors mediating the T-cell response has been an appealing strategy
for therapeutic exploitation [80,81] .

Among the multitude of immune checkpoint molecules under current investigation and development for
GB, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) are the most
popular given the favorable outcomes achieved for other tumors through their inhibition, leading to FDA
approval [82-86] . Studies have suggested the ability of these immune checkpoint inhibitors to overcome the
blood-brain barrier for activity within the CNS [87-90] .

In the context of GB, their inhibition showed promise in preclinical trials [91-95] .

Although the first phase III study of PD pathway inhibition, the Checkmate 143 trial failed to meet its
primary endpoint, several studies have focused on immune checkpoint inhibition for GB patients [96-98] .

As well as the enthusiasm for therapeutic exploitation of immune checkpoint blockade, there have also been
important concerns about immune-related toxicity profile of immune checkpoint inhibitors, partly due to