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n2:pmcid
PMC0
bibo:doi
10.1186%2Fs40425-017-0257-y
n8:contains
_:vb65793731 _:vb65793753 _:vb65793762 _:vb65793706 _:vb65793720 _:vb65793723
Subject Item
_:vb65793706
rdf:type
n8:Section
dc:title
background
n8:contains
_:vb65793708 _:vb65793709 _:vb65793710 _:vb65793711 _:vb65793707 _:vb65793716 _:vb65793717 _:vb65793718 _:vb65793719 _:vb65793712 _:vb65793713 _:vb65793714 _:vb65793715
Subject Item
_:vb65793707
rdf:type
n2:Context
rdf:value
Macrophages are known to be a highly plastic cell type that adapts to the particular stromal environment present in malignant tumors, characterized by tissue necrosis, low oxygen pressure, and high concentrations of lactate and pyruvate [>>1<<]. Macrophages have been described as responding to this micromilieu with either a pro-inflammatory or an anti-inflammatory phenotype (also referred to as “fight” versus “fix” macrophages, respectively) [2].
n2:mentions
n3:16864600
Subject Item
_:vb65793708
rdf:type
n2:Context
rdf:value
Macrophages have been described as responding to this micromilieu with either a pro-inflammatory or an anti-inflammatory phenotype (also referred to as “fight” versus “fix” macrophages, respectively) [>>2<<]. In early stage as well as metastatic cancer, the dominant tumor-associated macrophage (TAM) phenotype is reported to be anti-inflammatory, immune-regulatory, and therefore tumor-promoting (also termed alternatively activated or M2
n2:mentions
n3:23428224
Subject Item
_:vb65793709
rdf:type
n2:Context
rdf:value
M2 macrophages/TAM have been reported to promote tumor growth, angiogenesis, invasion, and metastasis as well as resistance to therapy [>>3<<, 4]. In addition, TAM infiltration has been shown to have a negative prognostic relevance in most tumor types [5]. This phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1; or
n2:mentions
n3:25035953
Subject Item
_:vb65793710
rdf:type
n2:Context
rdf:value
M2 macrophages/TAM have been reported to promote tumor growth, angiogenesis, invasion, and metastasis as well as resistance to therapy [3, >>4<<]. In addition, TAM infiltration has been shown to have a negative prognostic relevance in most tumor types [5]. This phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1; or
n2:mentions
n3:25770924
Subject Item
_:vb65793711
rdf:type
n2:Context
rdf:value
In addition, TAM infiltration has been shown to have a negative prognostic relevance in most tumor types [>>5<<]. This phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1; or macrophage colony-stimulating factor [MCSF]) as well as the cluster of differentiation (CD)-4+ type 2 helper
n2:mentions
n3:24592992
Subject Item
_:vb65793712
rdf:type
n2:Context
rdf:value
tumoricidal functions and are generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2) and pro-inflammatory stimuli such as interferon (IFN)-γ, lipopolysaccharide, or tumor necrosis factor α [>>6<<] (Fig. 1).Fig.
n2:mentions
n3:21727904
Subject Item
_:vb65793713
rdf:type
n2:Context
rdf:value
CSF1R belongs to the type III protein tyrosine kinase receptor family, and binding of CSF1 or the more recently identified ligand, IL-34, induces homodimerization of the receptor and subsequent activation of receptor signaling [>>8<<]. As the intratumoral presence of CSF1R+ macrophages correlates with poor survival in various tumor types [5, 9], targeting CSF1R signaling in tumor-promoting TAM represents an attractive strategy to eliminate or repolarize these cells.
n2:mentions
n3:27068937
Subject Item
_:vb65793714
rdf:type
n2:Context
rdf:value
As the intratumoral presence of CSF1R+ macrophages correlates with poor survival in various tumor types [>>5<<, 9], targeting CSF1R signaling in tumor-promoting TAM represents an attractive strategy to eliminate or repolarize these cells.
n2:mentions
n3:24592992
Subject Item
_:vb65793715
rdf:type
n2:Context
rdf:value
As the intratumoral presence of CSF1R+ macrophages correlates with poor survival in various tumor types [5, >>9<<], targeting CSF1R signaling in tumor-promoting TAM represents an attractive strategy to eliminate or repolarize these cells.
n2:mentions
n3:23284651
Subject Item
_:vb65793716
rdf:type
n2:Context
rdf:value
For the latter, Holmgaard and colleagues provided evidence for MDSC reprogramming towards a proinflammatory, tumoricidal phenotype upon treatment with a CSF1R small-molecule inhibitor, PLX3397 [>>10<<]. However, a clear interpretation of the role of MDSCs in inflammatory responses remains challenging because of the phenotypic, morphological, and functional heterogeneity of these cells in mice and humans [11].
n2:mentions
n3:27211548
Subject Item
_:vb65793717
rdf:type
n2:Context
rdf:value
However, a clear interpretation of the role of MDSCs in inflammatory responses remains challenging because of the phenotypic, morphological, and functional heterogeneity of these cells in mice and humans [>>11<<]. As our understanding of the influence of CSF1/CSF1R-mediated signaling on human myeloid-derived cells other than macrophages is just emerging, the focus of this review is on TAM and current clinical efforts to specifically target
n2:mentions
n3:27381735
Subject Item
_:vb65793718
rdf:type
n2:Context
rdf:value
efficacy data are still limited, with the exception of compelling anti-tumor activity observed in diffuse-type tenosynovial giant cell tumors (dt-GCT), a benign connective tissue disorder driven by CSF1 in an autocrine fashion [>>12<<]. The individual CSF1R inhibitors and their different drug-targeting properties have recently been reviewed [13].
n2:mentions
n3:26179200
Subject Item
_:vb65793719
rdf:type
n2:Context
rdf:value
The individual CSF1R inhibitors and their different drug-targeting properties have recently been reviewed [>>13<<]. Only two clinical-stage programs are currently targeting CSF1. No molecules targeting IL-34, the second-known ligand for CSF1R, are in clinical development thus far. We use “CSF1R inhibitor” as a general term for both receptor- and
n2:mentions
n3:24898549
Subject Item
_:vb65793720
rdf:type
n8:Section
dc:title
clinical activity with csf1r inhibitor monotherapy
n8:contains
_:vb65793721 _:vb65793722
Subject Item
_:vb65793721
rdf:type
n2:Context
rdf:value
melanomaNCT02975700Ongoing-2PlexxikonAdvanced castration-resistant prostate cancer with bone metastasis and high circulating tumor cell countsNCT01499043Not yet reported-2PlexxikonRecurrent GBMNCT01349036ORR: 0%CBR: 7/38 (18%)[>>14<<, 26]1/2NCIRefractory leukemias and refractory solid tumors, including neurofibromatosis type 1-associated plexiform neurofibromasNCT02390752Ongoing-2PlexxikonRelapsed or refractory cHLNCT01217229ORR:
n2:mentions
n3:26449250
Subject Item
_:vb65793722
rdf:type
n2:Context
rdf:value
Of 38 patients, seven (18%) experienced stable disease; no partial or complete responses were observed [>>14<<]. An objective response rate (ORR) of 5% was reported with single agent PLX3397 in 20 heavily pre-treated patients with cHL [15]. Comparable efficacy in relapsed or refractory cHL was demonstrated with JNJ-40346527 in a phase 1/2 clinical
n2:mentions
n3:26449250
Subject Item
_:vb65793723
rdf:type
n8:Section
dc:title
anti-tumor activity of csf1r inhibitors in diffuse-type tenosynovial giant cell tumor (dt-gct)
n8:contains
_:vb65793724 _:vb65793725 _:vb65793726 _:vb65793727 _:vb65793728 _:vb65793729 _:vb65793730
Subject Item
_:vb65793724
rdf:type
n2:Context
rdf:value
Initial clinical activity was seen in a dt-GCT patient who was treated with the BCR-ABL tyrosine kinase-targeting agent imatinib (Gleevec®) and achieved a complete response [>>20<<]. Thereafter, several phase I studies tested CSF1R-targeting compounds in selected dt-GCT patients as a proof-of-concept disease (Table 4).
n2:mentions
n3:18296418
Subject Item
_:vb65793725
rdf:type
n2:Context
rdf:value
in which 22 of 28 patients (79%) treated with the CSF1R-targeting mAb emactuzumab achieved a partial response, two patients (7%) had a complete response, three patients (11%) had stable disease, and no patient had disease progression [>>12<<]. Another study showed unconfirmed partial responses in four of four patients (100%) treated with the CSF1-targeting mAb MCS110 [21].
n2:mentions
n3:26179200
Subject Item
_:vb65793726
rdf:type
n2:Context
rdf:value
With the small-molecule inhibitor pexidartinib, 12 of 23 patients (52%) had a partial response, seven (30%) had stable disease, and one (4%) had progressive disease [>>22<<]. Responses in these studies were durable (>1 year for pexidartinib and >1.9 years for emactuzumab), and the median PFS had not been reached at the time of publication [12, 22]. A phase 3 study has started in patients with dt-GCT or giant
n2:mentions
n3:26222558
Subject Item
_:vb65793727
rdf:type
n2:Context
rdf:value
Responses in these studies were durable (>1 year for pexidartinib and >1.9 years for emactuzumab), and the median PFS had not been reached at the time of publication [>>12<<, 22]. A phase 3 study has started in patients with dt-GCT or giant cell tumor of the tendon sheath (GCT-TS) treated with pexidartinib versus placebo (ClinicalTrials.gov identifier NCT02371369). Although exciting clinical activity with
n2:mentions
n3:26179200
Subject Item
_:vb65793728
rdf:type
n2:Context
rdf:value
Responses in these studies were durable (>1 year for pexidartinib and >1.9 years for emactuzumab), and the median PFS had not been reached at the time of publication [12, >>22<<]. A phase 3 study has started in patients with dt-GCT or giant cell tumor of the tendon sheath (GCT-TS) treated with pexidartinib versus placebo (ClinicalTrials.gov identifier NCT02371369). Although exciting clinical activity with CSF1R
n2:mentions
n3:26222558
Subject Item
_:vb65793729
rdf:type
n2:Context
rdf:value
and the Patient-Reported Outcomes Measurement Information System (PROMIS) physical functioning items were introduced into clinical studies to investigate whether tumor shrinkage correlated with clinical benefit for these patients [>>12<<, 23]. Preliminary results from 22 patients treated with pexidartinib showed trends toward improvement in both pain and joint stiffness over time
n2:mentions
n3:26179200
Subject Item
_:vb65793730
rdf:type
n2:Context
rdf:value
Preliminary results from 22 patients treated with pexidartinib showed trends toward improvement in both pain and joint stiffness over time [>>24<<
n2:mentions
n3:27041409
Subject Item
_:vb65793731
rdf:type
n8:Section
dc:title
clinical safety and tolerability of csf1r inhibitors
n8:contains
_:vb65793736 _:vb65793737 _:vb65793738 _:vb65793739 _:vb65793740 _:vb65793741 _:vb65793742 _:vb65793743 _:vb65793732 _:vb65793733 _:vb65793734 _:vb65793735 _:vb65793752 _:vb65793744 _:vb65793745 _:vb65793746 _:vb65793747 _:vb65793748 _:vb65793749 _:vb65793750 _:vb65793751
Subject Item
_:vb65793732
rdf:type
n2:Context
rdf:value
In some studies no dose-limiting toxicities (DLTs) were reported [>>12<<, 18, 25], whereas others have observed DLTs defining a maximum tolerated dose (MTD) [17, 19, 22].
n2:mentions
n3:26179200
Subject Item
_:vb65793733
rdf:type
n2:Context
rdf:value
In some studies no dose-limiting toxicities (DLTs) were reported [12, 18, >>25<<], whereas others have observed DLTs defining a maximum tolerated dose (MTD) [17, 19, 22].
n2:mentions
n3:25628399
Subject Item
_:vb65793734
rdf:type
n2:Context
rdf:value
In some studies no dose-limiting toxicities (DLTs) were reported [12, 18, 25], whereas others have observed DLTs defining a maximum tolerated dose (MTD) [17, 19, >>22<<]. Overall, the adverse event (AE) profile of CSF1R inhibitors has been characterized quite extensively for the different compounds. Frequently reported AEs for both small molecules and mAbs include fatigue, elevated liver enzymes, facial
n2:mentions
n3:26222558
Subject Item
_:vb65793735
rdf:type
n2:Context
rdf:value
reported AEs for both small molecules and mAbs include fatigue, elevated liver enzymes, facial and peripheral edema, asthenia, pruritus, rash, nausea/vomiting, headache, dry skin, increased lacrimation, and decreased appetite [>>12<<, 17, 18, 22, 26–30]. Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 25–27, 30, 31].
n2:mentions
n3:26179200
Subject Item
_:vb65793736
rdf:type
n2:Context
rdf:value
AEs for both small molecules and mAbs include fatigue, elevated liver enzymes, facial and peripheral edema, asthenia, pruritus, rash, nausea/vomiting, headache, dry skin, increased lacrimation, and decreased appetite [12, 17, 18, >>22<<, 26–30]. Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 25–27, 30, 31].
n2:mentions
n3:26222558
Subject Item
_:vb65793737
rdf:type
n2:Context
rdf:value
AEs for both small molecules and mAbs include fatigue, elevated liver enzymes, facial and peripheral edema, asthenia, pruritus, rash, nausea/vomiting, headache, dry skin, increased lacrimation, and decreased appetite [12, 17, 18, 22, >>26<<–30]. Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 25–27, 30, 31].
n2:mentions
n3:19180511
Subject Item
_:vb65793738
rdf:type
n2:Context
rdf:value
Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [>>12<<, 17, 19, 22, 25–27, 30, 31].
n2:mentions
n3:26179200
Subject Item
_:vb65793739
rdf:type
n2:Context
rdf:value
Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, >>22<<, 25–27, 30, 31].
n2:mentions
n3:26222558
Subject Item
_:vb65793740
rdf:type
n2:Context
rdf:value
Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, >>25<<–27, 30, 31].
n2:mentions
n3:25628399
Subject Item
_:vb65793741
rdf:type
n2:Context
rdf:value
Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 25–27, 30, >>31<<]. Most studies reported that, despite elevations of these enzymes, patients did not experience clinical signs of liver toxicity, and bilirubin levels remained within the normal range [22, 27, 30, 31]. Short-lived elevations of liver
n2:mentions
n3:26233509
Subject Item
_:vb65793742
rdf:type
n2:Context
rdf:value
Most studies reported that, despite elevations of these enzymes, patients did not experience clinical signs of liver toxicity, and bilirubin levels remained within the normal range [>>22<<, 27, 30, 31].
n2:mentions
n3:26222558
Subject Item
_:vb65793743
rdf:type
n2:Context
rdf:value
Most studies reported that, despite elevations of these enzymes, patients did not experience clinical signs of liver toxicity, and bilirubin levels remained within the normal range [22, 27, 30, >>31<<]. Short-lived elevations of liver enzymes have also been observed in healthy volunteers [28]. The asymptomatic increases in liver enzymes with CSF1R-targeting treatment are most likely caused by a decrease in physiologic clearance through
n2:mentions
n3:26233509
Subject Item
_:vb65793744
rdf:type
n2:Context
rdf:value
Short-lived elevations of liver enzymes have also been observed in healthy volunteers [>>28<<]. The asymptomatic increases in liver enzymes with CSF1R-targeting treatment are most likely caused by a decrease in physiologic clearance through partial depletion of sessile macrophages of the liver (CSF1R+ Kupffer cells) [13, 32].
n2:mentions
n3:19180511
Subject Item
_:vb65793745
rdf:type
n2:Context
rdf:value
The asymptomatic increases in liver enzymes with CSF1R-targeting treatment are most likely caused by a decrease in physiologic clearance through partial depletion of sessile macrophages of the liver (CSF1R+ Kupffer cells) [>>13<<, 32]. Therefore, liver enzyme elevations can be considered a class effect of CSF1R-targeting compounds. In general, it seems this is not associated with functional liver impairment or structural damage to hepatocytes.
n2:mentions
n3:24898549
Subject Item
_:vb65793746
rdf:type
n2:Context
rdf:value
The asymptomatic increases in liver enzymes with CSF1R-targeting treatment are most likely caused by a decrease in physiologic clearance through partial depletion of sessile macrophages of the liver (CSF1R+ Kupffer cells) [13, >>32<<]. Therefore, liver enzyme elevations can be considered a class effect of CSF1R-targeting compounds. In general, it seems this is not associated with functional liver impairment or structural damage to hepatocytes.
n2:mentions
n3:21703406
Subject Item
_:vb65793747
rdf:type
n2:Context
rdf:value
For example, although facial edema is reported for up to 64% of patients treated with the mAb emactuzumab [>>12<<], it seems to occur to a lesser extent for the small molecule pexidartinib (seen in 26% of patients [22]), and periorbital edema was not reported in a phase 2 study in 63 rheumatoid arthritis patients treated with the small molecule
n2:mentions
n3:26179200
Subject Item
_:vb65793748
rdf:type
n2:Context
rdf:value
For example, although facial edema is reported for up to 64% of patients treated with the mAb emactuzumab [12], it seems to occur to a lesser extent for the small molecule pexidartinib (seen in 26% of patients [>>22<<]), and periorbital edema was not reported in a phase 2 study in 63 rheumatoid arthritis patients treated with the small molecule JNJ-40346527 [31].
n2:mentions
n3:26222558
Subject Item
_:vb65793749
rdf:type
n2:Context
rdf:value
to occur to a lesser extent for the small molecule pexidartinib (seen in 26% of patients [22]), and periorbital edema was not reported in a phase 2 study in 63 rheumatoid arthritis patients treated with the small molecule JNJ-40346527 [>>31<<]. Potentially immune-related AEs have been described for mAbs [12], whereas serious liver injuries have not been reported.
n2:mentions
n3:26233509
Subject Item
_:vb65793750
rdf:type
n2:Context
rdf:value
Potentially immune-related AEs have been described for mAbs [>>12<<], whereas serious liver injuries have not been reported.
n2:mentions
n3:26179200
Subject Item
_:vb65793751
rdf:type
n2:Context
rdf:value
hepatotoxicity may be triggered by inhibition of other receptor kinases, for example, as suggested by hair color changes with pexidartinib treatment in up to 74% of patients (likely due to inhibition of KIT kinase), remains unclear [>>22<<]. Potent KIT inhibitors such as dasatinib and pazopanib also cause ALT and AST elevations in about 50% of tumor patients, and hepatocellular necrosis has been shown in patients treated with pazopanib [34].
n2:mentions
n3:26222558
Subject Item
_:vb65793752
rdf:type
n2:Context
rdf:value
Potent KIT inhibitors such as dasatinib and pazopanib also cause ALT and AST elevations in about 50% of tumor patients, and hepatocellular necrosis has been shown in patients treated with pazopanib [>>34<<]. Hence, it cannot be ruled out that inhibition of tyrosine kinases other than CSF1R contribute to an aggravation of liver toxicities, particularly with small-molecule inhibitors.
n2:mentions
n3:23620168
Subject Item
_:vb65793753
rdf:type
n8:Section
dc:title
clinical combinations including csf1r inhibitors
n8:contains
_:vb65793754 _:vb65793755 _:vb65793756 _:vb65793757 _:vb65793758 _:vb65793759 _:vb65793760 _:vb65793761
Subject Item
_:vb65793754
rdf:type
n2:Context
rdf:value
Rational combination therapies investigating CSF1R inhibition have been investigated in preclinical cancer models (recently reviewed by Ries et al. [>>13<<]). Various small-molecule kinase inhibitors and antibodies directed against CSF1 or CSF1R were combined with chemotherapies, irradiation, anti-angiogenic or cancer immunotherapies using immunocompetent and immunodeficient mouse models.
n2:mentions
n3:24898549
Subject Item
_:vb65793755
rdf:type
n2:Context
rdf:value
(anti-PD1 mAb)1/2Plexxikon/Daiichi SankyoSolid tumors, malignant melanomaGIST, NSCLC, ovarian carcinoma, TNBC, SCCHN, UBC, pancreatic cancer, gastric carcinoma, leiomyosarcoma, cholangio carcinoma, CRC (MSS)NCT02452424Ongoing[>>74<<]Durvalumab (anti-PDL1 mAb)1Astra ZenecaPancreatic carcinoma, CRCNCT02777710Ongoing-CSF1RARRY-382Pembrolizumab (anti-PD1 mAb)1Array BioPharmaSolid tumors, melanoma, NSCLCNCT02880371Ongoing-CSF1RBLZ945PDR001 (anti-PD1 mAb)1/2NovartisSolid
n2:mentions
n3:25361990
Subject Item
_:vb65793756
rdf:type
n2:Context
rdf:value
The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antagonist ipilimumab was the first checkpoint inhibitor to demonstrate clinical activity that led to a first approval in metastatic melanoma in 2011 [>>36<<]. Anti-PD1 and anti-PDL1 mAbs such as nivolumab, pembrolizumab, or atezolizumab have proven superior efficacy over standard-of-care therapy in a variety of indications such as melanoma, non-small-cell lung cancer (NSCLC), bladder cancer,
n2:mentions
n3:20525992
Subject Item
_:vb65793757
rdf:type
n2:Context
rdf:value
anti-PDL1 mAbs such as nivolumab, pembrolizumab, or atezolizumab have proven superior efficacy over standard-of-care therapy in a variety of indications such as melanoma, non-small-cell lung cancer (NSCLC), bladder cancer, and others [>>37<<–42]. Despite the sustained and deep responses observed in some patients, the majority of cancer patients do not respond to these agents.
n2:mentions
n3:26952546 n3:26712084 n3:25399552 n3:27718784 n3:25482239 n3:26406148
Subject Item
_:vb65793758
rdf:type
n2:Context
rdf:value
CSFR1 blockade has been shown to reduce T-cell-suppressive TAM infiltrates [>>13<<, 18]. Therefore, CSF1R inhibitors represent a promising combination partner for T-cell-enhancing immunotherapies. Based on the widespread use of PD1 and PDL1 inhibitors across tumor entities, a variety of clinical trials combining these
n2:mentions
n3:24898549
Subject Item
_:vb65793759
rdf:type
n2:Context
rdf:value
ResultsReferenceSmall moleculesCSF1R (and cKIT, Flt3)Pexidartinib (PLX3397, PLX108-01)1PlexxikonSolid tumors and extension for MEC, dt-GCT, GIST, ATC, metastatic solid tumorsNCT01004861OngoingORR: 12/23 (52%)CBR: 19/23 (83%)[>>22<<]3Plexxikon/Daiichi Sankyodt-GCT or GCT-TSNCT02371369Ongoing-Monoclonal antibodiesCSF1REmactuzumab (RG7155)1RocheSolid tumors and dt-GCTNCT01494688ORR:
n2:mentions
n3:26222558
Subject Item
_:vb65793760
rdf:type
n2:Context
rdf:value
12/23 (52%)CBR: 19/23 (83%)[22]3Plexxikon/Daiichi Sankyodt-GCT or GCT-TSNCT02371369Ongoing-Monoclonal antibodiesCSF1REmactuzumab (RG7155)1RocheSolid tumors and dt-GCTNCT01494688ORR: 24/28 (86%)CBR: 27/28 (96%[>>12<<]CSF1RCabiralizumab (FPA008)1/2FivePrimedt-GCTNCT02471716Ongoing-CSF1MCS1102Novartisdt-GCT or GCT-TSNCT01643850OngoingORR:
n2:mentions
n3:26179200
Subject Item
_:vb65793761
rdf:type
n2:Context
rdf:value
Preclinically, Mok and coworkers reported that depletion of alternatively activated macrophages with pexidartinib improved the efficacy of adoptive cell transfer in a melanoma mouse model [>>43<<]. However, this combination has not been tested clinically. Other approaches include, for example, CSF1R inhibition within a triple combination with chemotherapy and anti-angiogenic treatment in platinum-resistant ovarian cancer
n2:mentions
n3:24247719
Subject Item
_:vb65793762
rdf:type
n8:Section
dc:title
local tissue macrophage and disease specificity impacting csf1r-directed treatment strategies
n8:contains
_:vb65793792 _:vb65793793 _:vb65793794 _:vb65793772 _:vb65793773 _:vb65793774 _:vb65793775 _:vb65793768 _:vb65793769 _:vb65793770 _:vb65793771 _:vb65793764 _:vb65793765 _:vb65793766 _:vb65793767 _:vb65793763 _:vb65793788 _:vb65793789 _:vb65793790 _:vb65793791 _:vb65793784 _:vb65793785 _:vb65793786 _:vb65793787 _:vb65793780 _:vb65793781 _:vb65793782 _:vb65793783 _:vb65793776 _:vb65793777 _:vb65793778 _:vb65793779
Subject Item
_:vb65793763
rdf:type
n2:Context
rdf:value
In the healthy lung, for instance, resident alveolar macrophages that develop from fetal monocytes are mainly regulated by the presence of local GM-CSF [>>44<<, 45]. Downstream of GM-CSF signaling, lung-specific transcription factor peroxisome proliferator-activated receptor (PPAR)-γ and nuclear repressor Bach2 are responsible for surfactant clearance in macrophages that are participating in
n2:mentions
n3:24043763
Subject Item
_:vb65793764
rdf:type
n2:Context
rdf:value
In the healthy lung, for instance, resident alveolar macrophages that develop from fetal monocytes are mainly regulated by the presence of local GM-CSF [44, >>45<<]. Downstream of GM-CSF signaling, lung-specific transcription factor peroxisome proliferator-activated receptor (PPAR)-γ and nuclear repressor Bach2 are responsible for surfactant clearance in macrophages that are participating in host
n2:mentions
n3:18551128
Subject Item
_:vb65793765
rdf:type
n2:Context
rdf:value
of GM-CSF signaling, lung-specific transcription factor peroxisome proliferator-activated receptor (PPAR)-γ and nuclear repressor Bach2 are responsible for surfactant clearance in macrophages that are participating in host defense [>>46<<–48]. This supports the hypothesis that alveolar macrophages in healthy steady state are predominantly of the immunostimulatory M1 macrophage subtype.
n2:mentions
n3:24127487 n3:17490408 n3:25263125
Subject Item
_:vb65793766
rdf:type
n2:Context
rdf:value
These cells produce Th1 cytokines and promote T-cell stimulation while expressing low levels of CSF1R and proving largely resistant to CSF1R inhibitors [>>13<<]. Two recent publications report high levels of CSF1R and low human leukocyte antigen-antigen D-related (HLA-DR) as well as increased levels of macrophage markers CD68 and CD163 and decreased levels of inducible nitric oxide synthase
n2:mentions
n3:24898549
Subject Item
_:vb65793767
rdf:type
n2:Context
rdf:value
leukocyte antigen-antigen D-related (HLA-DR) as well as increased levels of macrophage markers CD68 and CD163 and decreased levels of inducible nitric oxide synthase (iNOS) on myeloid cells derived from tumors of lung cancer patients [>>10<<, 49]. Thus, tumor cells may induce a reprogramming of steady-state alveolar macrophages from the M1, CSF1Rlow phenotype towards the M2, CSF1Rhigh phenotype, making this tumor type a good candidate for CSF1R-targeting therapies.
n2:mentions
n3:27211548
Subject Item
_:vb65793768
rdf:type
n2:Context
rdf:value
antigen-antigen D-related (HLA-DR) as well as increased levels of macrophage markers CD68 and CD163 and decreased levels of inducible nitric oxide synthase (iNOS) on myeloid cells derived from tumors of lung cancer patients [10, >>49<<]. Thus, tumor cells may induce a reprogramming of steady-state alveolar macrophages from the M1, CSF1Rlow phenotype towards the M2, CSF1Rhigh phenotype, making this tumor type a good candidate for CSF1R-targeting therapies.
n2:mentions
n3:26319408
Subject Item
_:vb65793769
rdf:type
n2:Context
rdf:value
However, the literature documents contradictory prognostic relevance of TAM in NSCLC [>>9<<]. This may in part be due to the different detection methods and markers used, but it is more likely that the contradictory reports indicate differences in the local TAM phenotypes in lung cancer subtypes. Depending on the predominant TAM
n2:mentions
n3:23284651
Subject Item
_:vb65793770
rdf:type
n2:Context
rdf:value
Recently, in vitro-differentiated CD206-expressing human macrophages were shown to be rescued from emactuzumab-induced depletion in the presence of IL-4 [>>50<<], demonstrating the importance of the local cytokine micromilieu.
n2:mentions
n3:27582524
Subject Item
_:vb65793771
rdf:type
n2:Context
rdf:value
Intestinal macrophages also originate from monocytes [>>51<<] but exhibit a reduced inflammatory activation state that allows the healthy co-existence with commensal bacteria achieved by locally produced autocrine IL-10 as well as regulatory T-cell-derived IL-10 production [52].
n2:mentions
n3:25151491
Subject Item
_:vb65793772
rdf:type
n2:Context
rdf:value
from monocytes [51] but exhibit a reduced inflammatory activation state that allows the healthy co-existence with commensal bacteria achieved by locally produced autocrine IL-10 as well as regulatory T-cell-derived IL-10 production [>>52<<]. This M2 macrophage phenotype is able to protect colon cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death [53] and is dependent on CSF1R-related signaling, which was demonstrated for
n2:mentions
n3:26681458
Subject Item
_:vb65793773
rdf:type
n2:Context
rdf:value
This M2 macrophage phenotype is able to protect colon cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death [>>53<<] and is dependent on CSF1R-related signaling, which was demonstrated for different species (i.e., mice, monkeys) and in human colorectal cancer (CRC) patients, where intestinal macrophages were reduced significantly with CSF1R-targeting
n2:mentions
n3:23029025
Subject Item
_:vb65793774
rdf:type
n2:Context
rdf:value
on CSF1R-related signaling, which was demonstrated for different species (i.e., mice, monkeys) and in human colorectal cancer (CRC) patients, where intestinal macrophages were reduced significantly with CSF1R-targeting therapy [>>13<<, 18, 54, 55]. This predominant immunosuppressed environment, together with the observed CSF1R dependency of intestinal macrophages, supports using CSF1R inhibition in CRC patients.
n2:mentions
n3:24898549
Subject Item
_:vb65793775
rdf:type
n2:Context
rdf:value
on CSF1R-related signaling, which was demonstrated for different species (i.e., mice, monkeys) and in human colorectal cancer (CRC) patients, where intestinal macrophages were reduced significantly with CSF1R-targeting therapy [13, 18, >>54<<, 55]. This predominant immunosuppressed environment, together with the observed CSF1R dependency of intestinal macrophages, supports using CSF1R inhibition in CRC patients.
n2:mentions
n3:23657400
Subject Item
_:vb65793776
rdf:type
n2:Context
rdf:value
CSF1R-related signaling, which was demonstrated for different species (i.e., mice, monkeys) and in human colorectal cancer (CRC) patients, where intestinal macrophages were reduced significantly with CSF1R-targeting therapy [13, 18, 54, >>55<<]. This predominant immunosuppressed environment, together with the observed CSF1R dependency of intestinal macrophages, supports using CSF1R inhibition in CRC patients.
n2:mentions
n3:20682855
Subject Item
_:vb65793777
rdf:type
n2:Context
rdf:value
However, again, available data on the prognostic relevance of macrophages in CRC patients are contradictory [>>56<<]. In contrast to stromal macrophages, peritumoral TAM showed an anti-tumor M1 macrophage phenotype in CRC [57]. The pro- or anti-tumor effect of TAM may therefore also depend on their localization within the TME. However, the degree of
n2:mentions
n3:26568685
Subject Item
_:vb65793778
rdf:type
n2:Context
rdf:value
In contrast to stromal macrophages, peritumoral TAM showed an anti-tumor M1 macrophage phenotype in CRC [>>57<<]. The pro- or anti-tumor effect of TAM may therefore also depend on their localization within the TME. However, the degree of CSF1R-signaling dependency of macrophages at these different locations is still unclear. In addition to the
n2:mentions
n3:21909876
Subject Item
_:vb65793779
rdf:type
n2:Context
rdf:value
In a CRC subset with high microsatellite instability (MSI-high), TAM infiltration correlated with higher immunity compared with microsatellite stable (MSS) tumors [>>58<<, 59]. Therefore, the MSI-high subset of patients may represent a promising target population in which to include CSF1R inhibition to boost pre-existing tumor immunity. Despite the lower number of TAM (and immune infiltrates in general) in
n2:mentions
n3:27228287
Subject Item
_:vb65793780
rdf:type
n2:Context
rdf:value
In a CRC subset with high microsatellite instability (MSI-high), TAM infiltration correlated with higher immunity compared with microsatellite stable (MSS) tumors [58, >>59<<]. Therefore, the MSI-high subset of patients may represent a promising target population in which to include CSF1R inhibition to boost pre-existing tumor immunity. Despite the lower number of TAM (and immune infiltrates in general) in MSS
n2:mentions
n3:25583798
Subject Item
_:vb65793781
rdf:type
n2:Context
rdf:value
In MSS CRC patients, a higher expression of genes involved with epithelial to mesenchymal transition (EMT) has been reported, an event that is associated with the invasiveness and spreading of tumor cells [>>60<<]. In addition to their immunoregulatory capacities, M2 macrophages can be key contributors to the priming of the pre-metastatic niche [61] by, for example, inducing cytokine-mediated EMT [57, 62] and matrix remodeling [63]. Whether CSF1R
n2:mentions
n3:26982367
Subject Item
_:vb65793782
rdf:type
n2:Context
rdf:value
In addition to their immunoregulatory capacities, M2 macrophages can be key contributors to the priming of the pre-metastatic niche [>>61<<] by, for example, inducing cytokine-mediated EMT [57, 62] and matrix remodeling [63].
n2:mentions
n3:21654748
Subject Item
_:vb65793783
rdf:type
n2:Context
rdf:value
In addition to their immunoregulatory capacities, M2 macrophages can be key contributors to the priming of the pre-metastatic niche [61] by, for example, inducing cytokine-mediated EMT [>>57<<, 62] and matrix remodeling [63].
n2:mentions
n3:21909876
Subject Item
_:vb65793784
rdf:type
n2:Context
rdf:value
In addition to their immunoregulatory capacities, M2 macrophages can be key contributors to the priming of the pre-metastatic niche [61] by, for example, inducing cytokine-mediated EMT [57, >>62<<] and matrix remodeling [63].
n2:mentions
n3:23480772
Subject Item
_:vb65793785
rdf:type
n2:Context
rdf:value
In addition to their immunoregulatory capacities, M2 macrophages can be key contributors to the priming of the pre-metastatic niche [61] by, for example, inducing cytokine-mediated EMT [57, 62] and matrix remodeling [>>63<<]. Whether CSF1R blockade in MSS CRC patients is able to control the invasiveness and metastasis remains to be investigated.
n2:mentions
n3:27697834
Subject Item
_:vb65793786
rdf:type
n2:Context
rdf:value
They are scavengers for non-functional synapses [>>52<<, 64, 65], and CSF1R-mediated signaling is required both during early CNS development [66] and for survival in adults [67].
n2:mentions
n3:26681458
Subject Item
_:vb65793787
rdf:type
n2:Context
rdf:value
They are scavengers for non-functional synapses [52, >>64<<, 65], and CSF1R-mediated signaling is required both during early CNS development [66] and for survival in adults [67].
n2:mentions
n3:27049947
Subject Item
_:vb65793788
rdf:type
n2:Context
rdf:value
They are scavengers for non-functional synapses [52, 64, >>65<<], and CSF1R-mediated signaling is required both during early CNS development [66] and for survival in adults [67].
n2:mentions
n3:21068834
Subject Item
_:vb65793789
rdf:type
n2:Context
rdf:value
They are scavengers for non-functional synapses [52, 64, 65], and CSF1R-mediated signaling is required both during early CNS development [66] and for survival in adults [>>67<<]. Inhibition of CSF1R signaling via small molecules BLZ9445 [68] or PLX3397 [69] leads to profound depletion of microglia in the CNS without overt behavioral abnormalities or reduced performance in cognitive function in mice. Although of
n2:mentions
n3:20966214
Subject Item
_:vb65793790
rdf:type
n2:Context
rdf:value
Inhibition of CSF1R signaling via small molecules BLZ9445 [>>68<<] or PLX3397 [69] leads to profound depletion of microglia in the CNS without overt behavioral abnormalities or reduced performance in cognitive function in mice.
n2:mentions
n3:24056773
Subject Item
_:vb65793791
rdf:type
n2:Context
rdf:value
Inhibition of CSF1R signaling via small molecules BLZ9445 [68] or PLX3397 [>>69<<] leads to profound depletion of microglia in the CNS without overt behavioral abnormalities or reduced performance in cognitive function in mice.
n2:mentions
n3:24742461
Subject Item
_:vb65793792
rdf:type
n2:Context
rdf:value
In contrast to the contradictory reports for lung and CRC, the presence of TAM in human gliomas seems to be exclusively associated with tumor growth, grade, and poor prognosis [>>70<<, 71]. Targeting of microglia using BLZ9445 resulted in improved survival and regression of tumors in a mouse proneural GBM model. In this tumor model, CSF1R blockade did not result in depletion of microglia as in healthy control mice.
n2:mentions
n3:16775224
Subject Item
_:vb65793793
rdf:type
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In contrast to the contradictory reports for lung and CRC, the presence of TAM in human gliomas seems to be exclusively associated with tumor growth, grade, and poor prognosis [70, >>71<<]. Targeting of microglia using BLZ9445 resulted in improved survival and regression of tumors in a mouse proneural GBM model. In this tumor model, CSF1R blockade did not result in depletion of microglia as in healthy control mice. Here,
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anti-CSF1R treatment led to acquired resistance driven by elevated macrophage-derived insulin-like growth factor 1 (IGF-1) and high IGF-1 receptor (IGF-1R) levels on tumor cells, resulting in enhanced glioma cell survival and invasion [>>72<<]. Whether high IL-4 levels together with CD206 expression on TAM may also play a role in this acquired resistance to CSF1R inhibition in GBM is currently unknown.
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