Table 2.

Molecular targets and therapeutics targeting microglia and macrophages

Molecular target	Affected processes	Pharmaceutical	Trials in glioma	Trials in brain metastases
CSF1R	Recruitment and enhancement of cancer invasion 4,103,126	Pexidartinib BLZ945	Phase II trial: lacking activity in comparison with historical controls 97	Limited; the phase I trial showed good activity in breast cancer 105, included in the adaptive phase II clinical trial 127.
αvβ3 and αvβ5 integrins	Microglia-assisted angiogenesis; polarization of microglia 128	Cilengitide	Phase III trial: lacking activity in comparison with temolozomide 101	Minimal to none clinical activity in metastatic melanoma and pancreatic cancer 106,107
Immune check point inhibitors	PD-1 or PDL1 CTLA-4	Nivolumab or/and ipilimumab	Phase III trial: lacking activity in comparison with bevacizumab 129	Nivolumab + ipilimumab combination is active in melanoma brain metastases 119,120, nivolumab is safe and active in NSCLC and renal cell carcinoma brain metastases 121,122
AXL kinase	AXL kinase regulates PD-1 expression 130	BGB324 alone or with Nivolumab	Inhibits glioma xenographs in pre-clinical trials 103	Not tested
mTOR	Polarization towards tumor-permissive phenotypes 131	Everolimus	Phase II trial: lacking activity in comparison with historical controls 132	Everolimus, lapatynib, and capecytabine combination had some activity in breast cancer brain metastases 110; safe and effective in renal cell carcinoma brain metastases 109
		Temsirolimus	Phase II trial: not superior to temolozomide but phosphorylation of mTORSer2448 can influence response 133	Safe and effective in renal cell carcinoma brain metastases 109
VEGF	TAMs chemotaxis and proliferation 115	Bevacizumab	Improves PFS but not OS in newly diagnosed glioblastoma 134	Encouraging results of various combinations in phase II trials with patients with brain metastases from NSCLC, breast cancer and colorectal cancer 112-114
		Regorafenib	Improves PFS and OS in previously treated glioblastoma 135	In phase III trials, regorafenib significantly increased OS, and PFS of patients with metastatic colorectal cancer 136
Histone deacetylase	Effects dependent on dose or cell types 137; TAMs polarization 116	Vorinostat	Improved OS when compared with historical results, a subgroup of patients with clear benefit 138	Promising results in preclinical models of triple-negative breast cancer 139
		Valproate	Increased survival in observational studies 140 and in comparison with historical cohorts 141
		Romidepsin	Augmented temozolomide sensitivity in human glioma cells 139; lacking clinical activity 142

PFS, progression free survival; OS, overall survival