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Page 2 of 11 Sager et al. Neuroimmunol Neuroinflammation 2018;5:25 I http://dx.doi.org/10.20517/2347-8659.2018.12

significant median overall survival (OS) benefit with addition of temozolomide (TMZ) to conventionally
fractionated radiation therapy (RT), making adjuvant chemoradiotherapy followed by adjuvant TMZ the
standard of care for newly diagnosed GB patients . However, disease recurrence is exceedingly common
[2]
despite multimodal management. Repeat surgery, systemic agents and RT may be used in the recurrent
setting as salvage therapeutic options, nevertheless, the clinical course is typically progressive with almost
all patients ultimately succumbing to their disease .
[3-5]

Several treatment strategies are being explored to improve outcomes of patients with GB. Among these,
immunotherapy deserves utmost attention with several studies assessing its role in GB management. Herein,
we present a concise review of immunotherapy for GB.

MAIN IMMUNOTHERAPY APPROACHES FOR GB
Given the infiltrating nature of GB, diffuse microscopic disease may be typically present beyond the tumor
bulk at initial presentation. Thus, a successful therapy should specifically address the infiltrative tumor
stem cells surviving after implemented treatments such as surgery, chemotherapy and RT. Immunotherapy
may conceptually take part in achieving this task, on the premise that it may facilitate combating with
resistant GB cells through boosting of the host immune system. While the central nervous system (CNS)
has traditionally been thought of as an immune-privileged site due to prevention of cellular and molecular
diffusion by the blood-brain barrier and absence of lymphatic drainage, our understanding is being refined
with emerging evidence . The presence of a functional CNS lymphatic system has been reported recently
[6-8]
and enhanced the focus on immunotherapy for brain tumors .
[9]
Herein, we review main strategies for GB immunotherapy.

Cytokine therapy
The rationale of cytokine therapy is activation of the immune system through administration of
immunomodulatory cytokines. Cytokines are secreted or membrane-bound proteins and potent
immunomodulators with a critical role in immune system coordination [10-13] . Anti-tumor activities of cytokines
have been reported in animal studies paving the way for consequent cytokine-based cancer treatment strategies.
Among the multitude of cytokines including interleukins, interferons and hematopoietic growth factors, FDA
approval is currently available for interferon alpha for adjuvant treatment of melanoma and for high-dose,
bolus interleukin (IL)-2 for management of metastatic melanoma and renal cell cancer .
[13]
An important issue in cytokine therapy is to achieve effective concentrations in the tumor without
causing excessive toxicity. While local delivery by viral vectors has resulted in limited success for gliomas,
intratumoral injection of IL-2 secreting allogeneic fibroblasts into GL261 tumors in mice has achieved
increased survival [14-18] . Also, while IL-2 can induce over-differentiation of T cells and induce apoptosis of
activated T cells, it may also activate CD4+ FoxP3 TREG regulatory cells, thereby inhibiting T cell activation
and tumor killing activity. In this context, IL-7, IL-15, and IL-21 may also be used.

Liposomes and biopolymer microspheres are alternative routes utilized for intratumoral delivery of
cytokines. Also, cytokines have been used for delivery of toxins in an effort to combat glioma cells with
considerable success [19-21] .

Utility of cytokine immunotherapy in combination with other therapeutic modalities is being investigated
to exploit the synergistic activity against GB cells . Briefly, cytokine immunotherapy has achieved
[22]
encouraging results despite the need for further supporting robust evidence.