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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 9 of 13

Clinical evidence
Nivolumab Biologic PD-1 Phase III No superior survival [19]
FDA and EMA approved (mAb) vs. bevacizumab

BLZ945/PDR001 Small MW com- CSF-1R/PD1 Phase I/II Clinicaltri-
Investigational pound/ als.
Biologic (mAb) gov
PLX3397 Small MW compound CSF-1R ↓ Iba1+ cells Phase II No significant [38]
Investigational within the (recurrent effects on PFS com-
tumors glioblastoma) pared with histori-
cal controls
Cilengitide Synthetic cyclic RGD avβ3 and avβ5 Phase III No superior survival [45,46]
Investigational pentapeptide integrins vs. TMZ alone
(in combination with
TMZ)

In the table we reported the main features of drugs that interferes with biological functions of GAMs (name, characteristics and
molecular target) together with the pharmacological actions on GAMs and the clinical outcomes on glioblastoma. Drugs are listed based
on the level of evidence, i.e., preclinical (in vitro and in vivo) or clinical testing, according to the following criteria: (1) approved for clinical
use (1st, small molecular weight compounds, 2nd biologics); and (2) investigational drugs (1st, small molecular weight compounds, 2nd
biologics). ↑: increased; ↓: reduced. AmpB: amphotericin B; ARG1: arginase 1; BBB: blood-brain-barrier; CD: cluster of differentiation; CCL2:
chemokine (C-C motif) ligand 2; CCR5: C-C chemokine receptor type 5; CHA: chlorogenic acid (5-caffeoylquinic acid); CsA: cyclosporine
A; CSFs: colony stimulating factors; CSF1: macrophage colony stimulating factor; CSF1R: M-CSF receptor; CSF2R: GM-CSF receptor;
CSF2: granulocyte/macrophage colony stimulating factor; GAMs: glioma associated microglia/macrophages; GM-CSF: granulocyte/
macrophage colony stimulating factor; GSCs: glioblastoma cancer stem cells; JAK: Janus kinase; HGF: hepatocyte growth factor; Iba1:
ionized calcium-binding adapter molecule 1, i.e., a specific myeloid lineage marker; IFNγ: interferon γ; IL: interleukin; iNOS: inducible
nitric oxide synthase; mAb: monoclonal antibody; MAPK: mitogen-activated protein kinase; MCP: monocyte chemotactic protein; M-CSF:
macrophage colony stimulating factor; MDSCs: myeloid-derived suppressor cells; mTOR: mechanistic target of rapamycin kinase; MMP:
matrix metalloprotease; miRNA, or miR: microRNA; NFAT1: nuclear factor of activated T cells; MW: molecular weight; PFS: progression
free survival; PG: prostaglandin; PI3K: phosphoinositide 3-kinase; PD-1: programmed death-1; rAAV2: recombinant adeno-associated viral
vector; SDF-1: stromal-derived factor-1; SPP1: osteopontin; STAT: signal transducer and activator of transcription; TGFβ: transforming
growth factor β; TMZ: temozolomide; TOPO-II: topoisomerase-II; TRAM-34: 1-(2-chlorophenyl) diphenylmethyl-1H-pyrazole; Tregs:
regulatory T cells; VEGF-A: vascular endothelial growth factor-A; X7Ab: single chain antibody

eral strategies attempt to overcome this restriction such as improved drug formulation (i.e., nanoparticles or
lipid based formulation), local drug delivery (including gene therapy [61,62] ), or transient BBB permeabiliza-
tion [83,84] , to name a few. Among the above mentioned drugs, minocycline and rapamycin for example, have
increased BBB penetration properties; and novel mTOR inhibitors with improved pharmacokinetic proper-
ties are also under development. It is possible to envision the use of pharmacological compounds, targeting
GAMs’ functions, as a complement to current available therapeutic approaches.

DECLARATIONS
Authors’ contributions
Conceived the paper and wrote the primary draft: Dello Russo C
Contributed to the literature revision and manuscript editing: Cappoli N
Read and approved the final manuscript: Dello Russo C, Cappoli N

Availability of data and materials
Not applicable.

Financial support and sponsorship
Research on GAMs has been in part funded by Fondi di Ateneo 2014-2016, grants awarded to DRC.

Conflicts of interest
All authors declared that there are no conflicts of interest.