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Page 2 of 16 Pearce et al. Neuroimmunol Neuroinflammation 2018;5:47 I http://dx.doi.org/10.20517/2347-8659.2018.46

INTRODUCTION
Gliomas arise from different glial cell populations and can manifest as astrocytic tumors (astrocytoma,
anaplastic astrocytoma, and glioblastoma), oligodendrogliomas, ependymomas, and mixed gliomas.
Glioblastoma multiforme (GBM) is the most malignant, invasive, and common glioma, accounting for
over 50% of all diagnosed brain tumors. A patient with GBM possesses poor prognosis, as typical survival
is 14-15 months following diagnosis. Standard treatment includes surgical resection, radiation therapy,
[1]
and chemotherapy [temozolomide (TMZ)], but these often result in limited success . This is partially due
to treatment limitations, including infiltration of GBM cells to surrounding brain tissue, intratumoral
[2]
heterogeneity, and therapy passage across the blood brain barrier (BBB) .
The central nervous system (CNS) has long been considered an immune-privileged site, evidenced by
the presence of the BBB, lack of lymphatic vessels, and absence of major histocompatibility complex
[3]
(MHC) - positive antigen presenting cells (APCs) . However, recent work suggests that the CNS has a
closer relationship with the peripheral immune system. Soluble antigens of the cerebrospinal fluid drain
[4]
into the cervical lymph nodes, providing T cells activation before transport to the site of inflammation .
Leukocytes are known to gain partial access to the CNS through the choroid plexus, across the superficial
[5,6]
leptomeningeal vessels, and into the perivascular space . Brain tumor progression further compromises
[7]
the integrity of the BBB, allowing these T cells access to the brain . Given that immune cells can permeate
the BBB while maintaining cancer cell-specific targeting, immunotherapies have begun to establish their
promise in GBM treatment.

In this review, we will examine recent advances made in immunotherapies for GBM, focusing on harnessing
apoptotic functions in natural killer (NK) cells, blocking checkpoint inhibitors to unmask malignancies, and
inducing systemic response by vaccine administration to target tumors. We will also highlight clinical trials
using these immunotherapies. Finally, we will address therapy challenges and discuss the need for further
refinement in applications specific to brain tumors.

T-CELLS
+
+
The ratio of CD4 and CD8 T-cells is a prognostic marker in many malignancies and has been found to
[8]
inversely correlate with progression-free survival and overall survival (OS) in GBM , demonstrating an
avenue for immunotherapy intervention.
+
+
T-cells maturing in the thymus may develop into CD4 or CD8 T-cells, also known as helper T-cells
or cytotoxic T-cells, respectively. They are activated upon APC interaction. APCs recognize pathogen-
associated molecular patterns (PAMPs) via pattern recognition receptors, such as toll-like receptors. Once
PAMPs are recognized before or during endocytosis, antigens, usually peptides, are loaded onto MHC-I
or MHC-II proteins. Antigens that are loaded onto MHC-II proteins activate CD4 T-cells, which further
+
+
activate CD8 T-cell responses. This contrasts with antigens that are loaded onto MHC-I proteins, which
+
[9]
activate only CD8 T-cells .
[10]
+
Induction of helper T-cell differentiation from CD4 T-cells is orchestrated by cytokine stimulation . Helper
T-cells promote anti-tumor response by secreting pro-inflammatory cytokines interferon (IFN)-γ and tumor
necrosis factor (TNF). These cytokines then activate death receptors on the tumor cell surface, consequently
triggering dendritic cell (DC) cytotoxic functions. It is these functions that eradicate tumor cells. T
regulatory cells (Tregs) often modulate the immune response through the secretion of anti-inflammatory
cytokines tumor growth factor-β and interleukin (IL)-10. While Treg cytokine secretion is aimed to prevent
a dramatic immune response, Tregs may inadvertently contribute to tumor development by suppressing pro-
[11]
inflammatory anti-tumor responses .