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Dello Russo et al. Neuroimmunol Neuroinflammation 2018;5:36 I http://dx.doi.org/10.20517/2347-8659.2018.42 Page 5 of 13

relevant antiproliferative effects on different preclinical models of glioblastoma. The drug, namely BGB324
(also known as R428) significantly increased neurological free survival particularly in the group of mice
[37]
bearing high-AXL expressing tumors . In addition, BGB324 treatment reduced the amount of infiltrating
+
CD45 leukocytes and CD11b GAMs. Interestingly, the anti PD-1 inhibitor nivolumab increased the protec-
+
[37]
tive effects of BG324, and effectively prolonged the survival of tumor bearing mice . Nivolumab per se dis-
played no survival benefits in these animals, while increasing both AXL kinase activity and GAMs’ tumor
infiltration. In line with these observations, a phase III clinical trial (NCT02017717) set to compare the ef-
ficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent
[19]
glioblastoma failed to demonstrate its efficacy . Immune PD-1 check point inhibitors, including nivolumab,
have proven efficacy in various malignancies and the number of clinical approved indications is constantly
[41]
increasing . The use of these drugs is associated with specific toxicities, often termed immune-related ad-
verse events. The most common side effects involve the skin, colon, endocrine organs and liver. Rarely, neu-
[41]
rological complications have been described , including recent case reports on nivolumab-induced autoim-
[42]
[43]
mune encephalitis and progressive multifocal leukoencephalopathy .
Finally, microglial/macrophages’ infiltration of GSC-derived tumors was efficiently blocked by the integrin
[44]
inhibitor arginine-glycine-aspartic acid (RGD) peptides albeit interfering with GSC-secreted periostin .
Consistently, genetic ablation of periostin reduced GAMs’ recruitment at tumor site and modulated their im-
mune functions, thus inhibiting tumor growth and increasing survival of glioma bearing animals. Similar
beneficial effects were expected by pharmacological inhibition of integrin signaling pathways in human glio-
blastoma. However, despite promising phase I/II results, a recent phase III clinical trial failed to demonstrate
clinical efficacy of cilengitide, a cyclic RGD pentapeptide that selectively inhibits the avβ3 and avβ5 integrins
[45]
when added to standard temozolomide treatment in glioblastoma patients . A possible explanation for
[46]
these negative findings can be retrieved in part in the unfavorable pharmacokinetic profile of cilengitide .
In fact, the relevance of the signaling pathways downstream the integrin receptors, αvβ3 and αvβ5, is further
supported by a recent proteomic analysis of the glioma secretome. These data suggest the involvement of os-
teopontin (SPP1) and lactadherin in the reprogramming of GAMs’ immune responses towards pro-tumoral
[47]
functions via integrin signaling .

Drugs that interfere with GAMs’ inflammatory activation and immune function
Under the influence of glioma cells, the antitumor functions of GAMs appear mostly suppressed. As shown
in Figure 1, tumor cells indeed produce several immunosuppressive molecules, such as TGFβ, IL-10, and
various prostaglandins (i.e., prostaglandin E2, PGE2), thus favoring the acquisition of a pro-tumorigenic
phenotype of activation by GAMs [30,48,49] . Pharmacological strategies that promote antitumor activities of
GAMs, i.e., production of cytotoxic molecules and increased phagocytosis, or that reduce the release of pro-
tumorigenic (i.e., growth factors) may exert beneficial effects in glioblastoma. In this regard, amphotericin
[50]
B (AmpB), an antifungal compound clinically used to treat life-threatening fungal infections , has been
shown to promote macrophage activation via toll like receptor activation and increase pro-inflammatory
[51]
cytokine release . In view of these properties, AmpB was recently tested in preclinical models of gliomas.
In an experimental model consisting of human-derived GSC tumors implanted in nonobese diabetic/severe
combined immunodeficiency (NOD-SCID) mice, systemic administration of AmpB significantly reduced
[52]
tumor growth and increased animal survival . The drug did not exert direct anti-tumor activity on GSCs
in vitro and its pharmacological benefits in vivo were abated by depletion of myeloid cells. This suggests that
the beneficial effects of AmpB were mediated by modulation of GAMs’ functions. Increased tumor infiltra-
+
tion of Iba1 microglial cells and macrophages was detected in AmpB treated animals. This effects has been
recently confirmed using ultrasmall iron oxide nanoparticles as contrast agents for magnetic resonance im-
+
[53]
aging, in order to detect monocyte infiltration into brain tumors . In addition, tumor infiltrating Iba1 cells
in response to AmpB showed a significant up-regulation of iNOS, that most likely results in increased pro-
[52]
duction of cytotoxic nitric oxide (NO) Beneficial effects of AmpB were also observed in immunocompe-