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Page 2 of 18 Yelton et al. Neuroimmunol Neuroinflammation 2018;5:46 I http://dx.doi.org/10.20517/2347-8659.2018.58

[1]
clinicians and researchers alike. Classified as a grade IV glioma by the World Health Organization (WHO)
this tumor’s dismal survival rates are owed to its ability to recur following first-line treatment strategies such
as surgical resection, radiation therapy, and chemotherapeutic agents - the current standard of care. This
tumor also possesses the ability to evade current first-line treatment strategies through the development of
[2]
multiple resistance mechanisms, which it employs to recur despite initial response to these strategies . GBM
is also simply called glioblastoma. The most resistant glioblastoma cells, also known as glioblastoma stem
cells (GSCs), which remain alive following first-line therapy have employed resistance mechanisms and will
go on to form recurrent glioblastomas. These tumors are more difficult to treat as they confer resistance to
first-line treatment strategies, requiring alternative therapies. The agents currently needed to combat these
recurrent glioblastomas are lacking. As such, developing novel therapeutic agents based on inquiries into
the biochemical specificities and pathogeneses of these tumors has been a hotbed of research in recent years.
Novel therapeutic agents have shown considerable promise in their developmental phases but have yet to
replace the current standard of care. The current standard of care includes surgical resection, radiotherapy,
[3]
and the chemotherapy using temozolomide (TMZ) . Multiple avenues have been explored for potential
therapeutic strategies. One particularly exciting avenue of research is immunotherapy, which harnesses the
[4,5]
immune system to aid in abolishing the growth of glioblastoma .
Immunotherapy has seen success in the clinical realm in recent years, a success that can be attributed to a
more robust understanding of basic tumor immunology in order to aid the immune system in fighting a
[6]
neoplastic process . Previously, the lack of clinical efficacy in immunotherapy was due to the ability of many
[7]
tumors to avoid recognition and therefore elimination by the immune system . However, active research in
this area into how the tumor evades the immune system has led to novel therapies in the fight against these
pathologies, with cancer immunotherapy even being heralded as the “breakthrough of the year” roughly five
[8]
years ago . Most recently, immunotherapy specific to malignancies has been such an exciting breakthrough
that Drs. James P. Allison and Tasuku Honjo have received the 2018 Nobel Prize in Physiology or Medicine
for their contributions to the field of cancer immunotherapy and identification of the immune checkpoint
proteins [e.g., programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), cytotoxic T lymphocyte
associated antigen-4 (CTLA-4)] that usually act as a brake on the immune system. For modulating
the immune system, these therapies have employed multiple strategies including inhibiting immune
checkpoints, expanding an existing immune system response, enhancing the immunological profile of solid
tumors, natural killer (NK) cell/chimeric antigen receptor (CAR)-T cell modulation, and T regulatory (Treg)/
[9]
myeloid suppressor cell modulation . Immunotherapy, like any other new treatment modality heralded as
panacea, ultimately has its limitations and downsides when being used to treat cancer. These limitations are
especially evident with glioblastoma, as certain modalities of cancer immunotherapy (immune checkpoint
inhibitors, CAR-T cell therapy, etc.) require continued research and further clinical trials if they are to be
considered in the next step in the targeted glioblastoma therapy [10,11] .

A challenge specific to glioblastoma and a potential barrier to the application of immunotherapy to
these tumors is the presence of the blood-brain barrier (BBB), which forms a protective coating around
the brain made up of tight junctions between astrocytes. Traditional dogma had considered the brain
to be an inaccessible site, due to rudimentary studies in the late 19th century, and early 20th century
[12]
with dyes injected into the blood not showing up in the brain upon autopsy . Years later, an extension
of this experimentally derived dogma also assumed that the CNS was among many tissues to be an
[13]
“immunoprivleged” site largely derived from studies of grafts transplanted in the CNS that failed to be
rejected when similarly grafted into other sites that were more immunologically accessible within the body.
Additionally, the brain’s lack of draining lymphatics, the apparent immunoincompetence of microglia (the
brain’s resident macrophages), and the assumption of CNS autoimmunity being a direct consequence from
CNS antigen encounter by an immune cell cemented the idea of the brain being an inaccessible sanctuary
[14]
away from the body’s immune system . However, today this is not believed to be the case. A physiologically
functioning BBB is now believed to act as a communication center of sorts, passing (and responding to)