Page 272 - Read Online

Page 4 of 13 Dello Russo et al. Neuroimmunol Neuroinflammation 2018;5:36 I http://dx.doi.org/10.20517/2347-8659.2018.42

[5]
renchyma . Therefore, pharmacological treatments that prevent or reduce GAMs’ recruitment at the tumor
site are expected to exert beneficial effects in glioblastoma. In this regard, it has been shown that the immu-
nosuppressant agent cyclosporine A (CsA), a drug normally used in clinical practice, significantly reduces
the number of infiltrating microglia/macrophages in implanted glioma tumors. This effect, together with a
[9]
modulation of GAM’s inflammatory activation, results in a significant reduction of tumor growth . Howev-
er, chronic immunosuppression associated with systemic use of CsA increases the risk of developing tumors,
and may probably limit the use of this drug for the treatment of glioblastoma. In addition, several tumor
favoring mechanisms are associated with CsA, including increased production of transforming growth fac-
[31]
tor β (TGFβ) and VEGF together with an inhibitory action on the DNA repairing ability of the cells . In
the human U-87 glioma cell line, CsA significantly reduced the expression level of the human microRNA
[32]
(miRNA, miR-)195, together with the modulation of several other miRNAs . Interestingly, miR-195 seems
to play a tumor suppressor function in both glioma cell lines and human gliomas [33,34] . On the other hand,
the nuclear factor of activated T cells (NFAT1), i.e., the main intracellular target of CsA, appears to be a cru-
cial regulator of glioma invasion-related genes. Thus, a direct inhibition of NFAT1 activity in glioma cells
can limit their ability to infiltrate normal brain parenchyma, and may be considered as a potential adjuvant
[35]
therapy for glioblastoma .
Interestingly, novel compounds, interfering with known chemoattractant factors, are in different stages
of development for the treatment of glioblastoma. For example, it has been shown that the CSF-1R inhibi-
tor BLZ945, which blocks the signaling pathways activated by M-CSF, significantly increased survival in
[36]
different preclinical models of glioblastoma . This pharmacological treatment induced the regression of
established tumors in engineered mice and abated tumor growth in human xenografts. The drug is a small
molecular weight CSF-1R inhibitor, with optimal BBB penetration properties. However, despite the chemoat-
tractant properties of M-CSF and its established role in promoting macrophage survival, BLZ945 did not
reduce the number of tumor infiltrating microglia/macrophages in these models. GAMs appeared indeed
protected from BLZ-induced cell death by glioma-secreted cytokines such as GM-CSF, interferon γ (IFNγ)
[36]
and the C-X-C motif chemokine 10 (CXCL10) . On the other hand, BLZ945 modulated the inflammatory
activation of GAMs, favoring their antitumor activities which explains the beneficial effects observed with
the treatment (see next section). In a different preclinical model of glioblastoma, consisting of tumors de-
rived by implantation of GSCs lacking tumor suppressor phosphatase and tensin homolog, p53 and neurofi-
bromin 1 (NF1), BLZ945 efficiently blocked GAMs’ recruitment at tumor site together with reducing tumor
[37]
growth . Interestingly, a first-in-human study employing BLZ945 (NCT02829723) is currently ongoing. It
is a phase I/II with BLZ945 given as a single agent or in combination with PDR001 [a novel monoclonal an-
tibody against the immune checkpoint programmed death-1 (PD-1) receptor, by Novartis Oncology], which
aims at the characterization of the safety, tolerability, pharmacokinetics, pharmacodynamics, and anti-
tumor activity of BLZ945 in adult patients with advanced solid tumors. Moreover, another selective CSF-
1R inhibitor (PLX3397) has been recently tested in a phase II clinical trial in patients affected by recurrent
glioblastoma (NCT01349036). The drug was well tolerated, showed good BBB penetration, and reduced the
+
amount of Iba1 cells within the tumors. However, no significant improvement in the progression free sur-
[38]
vival compared with historical controls was observed in PLX3397 treated patients . Moreover, it has been
recently shown that genetic reduction of MCP-1/CCL2 significantly reduces macrophage infiltration within
[39]
the tumors extending the survival time of tumor bearing animals . However, previous attempts to block
MCP-1/CCL2 with monoclonal antibodies demonstrated modest clinical efficacy. The drugs were instead
[27]
effective in combination with temozolomide, significantly increasing mice survival . Interestingly, it has
been shown that the production of MCP-1 by glioma cells can be efficiently reduced by non-cytotoxic drugs,
including the antibiotic minocycline, the angiotensin II receptor inhibitor telmisartan and the bisphospho-
[40]
nate zolendronic acid . These drugs have a good BBB penetration and will be tested in combination as an
ancillary therapy to improve the outcome of currently approved cytotoxic regimens.

Recently, a small molecular weight inhibitor of the AXL receptor tyrosine kinase has been shown to exert