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Sager et al. Neuroimmunol Neuroinflammation 2018;5:25 I http://dx.doi.org/10.20517/2347-8659.2018.12 Page 3 of 11

Passive immunotherapy
Serotherapy and adoptive immunotherapy are passive immunotherapy strategies. Passive immunotherapy is
based on delivering the patient immune cells or antibodies with the capability of targeting the tumor cells .
[23]
Unlike active immunotherapy in which the patient’s immune system is boosted, passive immunotherapy
doesn’t include activation of host immunity. Infusion of LAK cells into the tumor bed was an initial attempt
of passive immunotherapy in the earlier years [24,25] . Cytotoxic T lymphocytes (CTLs) were also studied for
adoptive immune response .
[26]

The use of monoclonal antibodies as a passive immunotherapy approach may result in killing of tumor
cells through different mechanisms . Sparing of normal brain tissue without tumor may be achieved if the
[27]
antigen targeted by the monoclonal antibody is specifically expressed by the tumor only. Vascular endothelial
growth factor (VEGF) is highly expressed in GB and targeted for therapeutic exploitation with bevacizumab
(BEV). As a recombinant humanized monoclonal antibody, BEV is bound to VEGF-A and exerts antitumor
effect. An improvement in progression free survival and maintenance in quality-of-life and performance
status has been reported with addition of BEV to RT and temozolomide .
[28]
Another potential target in GB is the epidermal growth factor receptor (EGFR) . EGFR gene mutation
[29]
typically in EGFR variant III (EGFRvIII) is very common in GB. In this context, the use of anti-EGFRvIII
antibodies in combined modality GB management is an area of active investigation.

Adoptive T-cell immunotherapy
Adoptive T-cell therapy offers an alternative immunotherapeutic approach. In this treatment, tumor-specific
autologous T-cells undergo in vitro amplification and are consequently infused to the same individual
for therapeutic exploitation. Advances in genetic engineering has paved the way for adoptive T-cell
immunotherapy through generation of high avidity tumor-specific T-cells . Chimeric antibody receptor
[30]
(CAR)-based treatments and cytomegalovirus (CMV) adoptive T-cell immunotherapy have great potential
for further therapeutic exploitation [31-35] .

A unique advantage of adoptive T-cell immunotherapy is the capability of expanding substantial amounts of
tumor infiltrating T lymphocytes (TILs) in vitro without immunosuppressive environments seen in vivo .
[36]
Adverse effects of adoptive T-cell immunotherapy may include cytokine release syndrome (CRS) and tumor
lysis syndrome (TLS) which underscore the importance of early detection of these syndromes through
vigilant monitoring [37,38] . CRS and neurotoxicity may be triggered by the inflammatory molecule IL-1, and
adding ANAKINRA, an inhibitor of IL-1, to the treatment regimen can block the molecule. Also, inserting
the IL-1 inhibitor gene directly into CAR-T cells may prevent CRS.

Active immunotherapy (peptide vaccines, dendritic cell vaccines, heat shock protein vaccines)
Active immunotherapy is based on the premise that vaccination against tumor antigen stimulates an adaptive
immune response against tumor cells. Target antigens include tumor-specific antigens (TSAs) expressed
solely by the tumor and tumor-associated antigens (TAAs) expressed by both tumor cells and normal cells.
While TSAs have a greater potential to evoke a more potent and specific immune response compared to
TAAs, they are exceedingly rare. EGFRvIII, IDH-1/2 mutations (e.g., R132H), and CMV proteins are known
TSAs expressed in GB and IL-13Rα2, HER-2, gp100, survivin, WT1, TRP2, EphA2, SOX2, SOX11, MAGE-A1,
MAGE-A3, AIM2, SART1, and tenascin are TAAs expressed in GB .
[10]
Heterogeneity of GBs warrants the demand for individualized, patient-specific and non-toxic
immunotherapies. Attracted by the success of vaccination against hormone-resistant metastatic prostate
cancer, researchers have focused on developing vaccines against GB . Herein, we review peptide vaccines,
[39]
dendritic cell (DC) vaccines, and heat shock protein (HSP) vaccines.