Open Access

Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy

  • Michael A. Cannarile1Email author,
  • Martin Weisser1,
  • Wolfgang Jacob1,
  • Anna-Maria Jegg1,
  • Carola H. Ries1 and
  • Dominik Rüttinger1
Contributed equally
Journal for ImmunoTherapy of Cancer20175:53

https://doi.org/10.1186/s40425-017-0257-y

Received: 10 February 2017

Accepted: 5 June 2017

Published: 18 July 2017

Abstract

The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ-specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future.

Keywords

CSF1 CSF1R Tumor-associated macrophage Clinical trial Cancer therapy PVNS Dt-GCT

Background

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]. 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 macrophages) as opposed to pro-inflammatory and tumoricidal (classically activated or M1 macrophages). We and others believe that the continuum of different macrophage phenotypes present within the tumor microenvironment (TME) is difficult to capture solely with the M1/M2 dichotomy. However, for simplicity reasons, we use the term M1 or M2 macrophage/TAM to differentiate two extreme functional phenotypes in this review. 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 macrophage colony-stimulating factor [MCSF]) as well as the cluster of differentiation (CD)-4+ type 2 helper T-cell-derived (Th2) cytokines interleukin (IL)-4, IL-13, and IL-10 in the TME. In contrast, M1 macrophages are ascribed 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. 1

Direct and indirect regulation of immune suppression or stimulation by tumor associated macrophage subtypes. Macrophage polarization within the tumor microenvironment is highly dependent on the local cytokine milieu which originates either from tumor cells, other stromal cells such as immune cells or fibroblasts, as well as macrophages themselves. The M2 TAM phenotype is a consequence of the continuous presence of growth factors such as colony-stimulating factor-1 (CSF1) as well as CD4+ T cell-derived Th2 cytokines interleukin (IL)-4, IL-13 and IL-10 (5). Besides the direct tumor growth promoting abilities of M2 TAM (not illustrated here), these macrophages efficiently suppress immune effector functions that are able to contribute to tumor cell elimination (3,4). This silencing of immune effector cells is achieved by producing cytokines and enzymes that may directly suppress effector cells or indirectly via other immune cell types such as intratumoral dendritic cells (DC), T regulatory cells (Treg cells) and Type 2 helper T cells. In contrast, M1 TAM are attributed with tumoricidal functions and are generated in the presence of GM-CSF and pro-inflammatory stimuli like IFNγ, LPS or TNFα (5). Tumoricidal function can either be achieved through direct killing of tumor cells or by producing cytokines/chemokines that are activating/recruiting other immune stimulatory immune cells and inhibiting immune suppressive cells like Treg cells. Eventually a predominant M1 TAM phenotype may result in an anti-tumor immune effector cell activation. Published data suggest that tumor promoting and immune suppressive M2 macrophages/TAM are dependent on CSF1R mediated signals (31) making this receptor an attractive target to eliminate or repolarize these cells

CSF1 receptor (CSF1R)-mediated signaling is crucial for the differentiation and survival of the mononuclear phagocyte system and macrophages in particular [7]. 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.

In addition to TAM, CSF1R expression can be detected on other myeloid cells within the tumor microenvironment such as dendritic cells, neutrophils, and myeloid-derived suppressor cells (MDSCs)

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]. 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 CSF1/CSF1R in cancer therapy. We also highlight the importance of site/organ and tumor-type specificities of TAM, which are now recognized as an important new frontier in cancer immunotherapy. Early clinical data suggest good tolerability of CSF1/CSF1R-targeting compounds; however, available 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]. 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 ligand-targeting compounds.

Clinical activity with CSF1R inhibitor monotherapy

A variety of small molecules and monoclonal antibodies (mAbs) directed at CSF1R or its ligand CSF1 are in clinical development both as monotherapy and in combination with standard treatment modalities such as chemotherapy as well as other cancer-immunotherapy approaches (Tables 13).
Table 1

CSF1/CSF1R inhibitors as monotherapy in current clinical development

Class

Target

Compound

Clinical Phase

Sponsor

Indication

ClinicalTrials.gov identifier

Status/Results

Reference

Small molecules

CSF1R (and cKIT, Flt3)

Pexidartinib (PLX3397, PLX108-01)

2

The Christie NHS Foundation Trust

KIT-mutated advanced acral and mucosal melanoma

NCT02071940

Ongoing

-

1/2

Plexxikon

Unresectable or metastatic KIT-mutated melanoma

NCT02975700

Ongoing

-

2

Plexxikon

Advanced castration-resistant prostate cancer with bone metastasis and high circulating tumor cell counts

NCT01499043

Not yet reported

-

2

Plexxikon

Recurrent GBM

NCT01349036

ORR: 0%

CBR: 7/38 (18%)

[14, 26]

1/2

NCI

Refractory leukemias and refractory solid tumors, including neurofibromatosis type 1-associated plexiform neurofibromas

NCT02390752

Ongoing

-

2

Plexxikon

Relapsed or refractory cHL

NCT01217229

ORR: 1/20 (5%)

[15]

1/2

Plexxikon

Relapsed or refractory FLT3-ITD-positive acute myeloid leukemia

NCT01349049

Ongoing

-

1

Plexxikon

Advanced, incurable, solid tumors in which the target kinases are linked to disease pathophysiology

NCT01004861

Ongoing

-

CSF1R (and Trk)

PLX7486

1

Plexxikon

Solid tumors

NCT01804530

Ongoing

-

CSF1R

ARRY-382

1

Array BioPharma

Solid tumors

NCT01316822

ORR: 0%

CBR: 4/26 (15%)

[17]

CSF1R

JNJ-40346527

1/2

Johnson& Johnson

cHL

NCT01572519

ORR: 1/21 (5%)

CBR: 11/21 (52%)

[16]

CSF1R

BLZ945

1/2

Novartis

Solid tumors

NCT02829723

Ongoing

-

Monoclonal antibodies

CSF1R

Emactuzumab (RG7155)

1

Roche

Solid tumors

NCT01494688

PMR: 5/44 (11%)

ORR: 0%

CBR: 6/40 (24%)

[18]

CSF1R

AMG820

1

Amgen

Solid tumors

NCT01444404

ORR: 1/25 (4%)

CBR: 6/25 (24%)

[19]

CSF1R

IMC-CS4 (LY3022855)

1

Eli Lilly

Solid tumors

NCT01346358

Ongoing

-

1

Eli Lilly

Breast and prostate cancer

NCT02265536

Ongoing

-

CSF1

MCS110

1/2

Novartis

Prostate cancer

NCT00757757

Terminated

-

CBR clinical benefit rate, cHL classical Hodgkin lymphoma, CSF1 colony-stimulating factor 1, CSF1R colony-stimulating factor 1 receptor, GBM glioblastoma, NCI National Cancer Institute, NHS National Health Service, ORR objective response rate, PMR partial metabolic response

Among the class of small molecules, pexidartinib (PLX3397), an oral tyrosine kinase inhibitor of CSF1R, cKIT, mutant fms-like tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptor (PDGFR)-β, is the subject of the broadest clinical development program in monotherapy, with completed or ongoing studies in c-kit-mutated melanoma, prostate cancer, glioblastoma (GBM), classical Hodgkin lymphoma (cHL), neurofibroma, sarcoma, and leukemias. Additional CSF1R-targeting small molecules, including ARRY-382, PLX7486, BLZ945, and JNJ-40346527, are currently being investigated in solid tumors and cHL. mAbs in clinical development include emactuzumab, AMG820, IMC-CS4, cabiralizumab, MCS110, and PD-0360324, with the latter two being the only compounds targeting the ligand CSF1.

A phase 2 study in 38 patients with recurrent GBM treated with pexidartinib did not show significant improvement in 6-month progression-free survival (PFS) compared to historical control data. 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 study. Out of 21 patients enrolled, one showed a complete response (ORR 5%) and 11 (52%) experienced stable disease [16].

Results from a phase 1 study investigating ARRY-382 in advanced solid tumors were recently reported by Bendell et al. Out of 26 patients, four (15%) had stable disease, and no objective responses were observed [17]. A phase 1/2 study with BLZ945 in solid tumors is ongoing.

Data from a phase 1 dose-escalation and expansion study investigating emactuzumab showed partial metabolic responses in fluorodeoxyglucose-positron emission tomography in 5/44 (11%) patients and stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) in 6/40 (15%) patients [18]. In addition, the study provided proof of mechanism, demonstrating significant TAM reduction with emactuzumab in paired pre- and on-treatment tumor biopsies (Fig. 2).
Fig. 2

Depletion of tumor-associated macrophages with emactuzumab in cancer patients. Immunohistochemistry of paired tumor biopsies from a representative ovarian cancer patient illustrating co-localization and reduction of CD68+CD163+ TAM (upper panel) and CSF1R+ cells (lower panel) after 4 weeks/two infusions of emactuzumab at the 1000 mg dose level. Permission for re-use granted by I. Klaman [18]

Papadopoulos et al. reported that 6/25 patients (24%) treated with AMG820 had a best overall response of stable disease, and one paraganglioma patient (4%) had a partial response, with a 40% reduction in tumor burden [19].

Results from two ongoing single-agent phase 1 studies of IMC-CS4 in solid tumors and breast and prostate cancer are pending. A phase 1/2 study in prostate cancer of the only anti-CSF1 antibody, MSC110, has been terminated; however, several clinical trials are underway with MSC110 in combination with chemotherapy or immune checkpoint inhibitor therapy (Tables 2 and 3).

Anti-tumor activity of CSF1R inhibitors in diffuse-type tenosynovial giant cell tumor (dt-GCT)

dt-GCT of the soft tissue (alternatively known as pigmented villonodular synovitis [PVNS]) is an orphan disease characterized by overexpression of CSF1 and is usually caused by chromosomal translocations involving chromosome 1p13 where the CSF1 gene is located. CSF1R activation leads to the recruitment of CSF1R-expressing macrophages that constitute a large part of the tumor mass in dt-GCT, thus making this pathway an ideal therapeutic target for compounds interfering with the CSF1/CSF1R-signaling axis. Unresectable dt-GCT is rarely, if ever, a lethal disease but rather a debilitating chronic illness of high unmet medical need, frequently requiring several surgical procedures.

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). Substantial clinical activity was observed in the study by Cassier et al. (2015), 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]. 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 cell tumor of the tendon sheath (GCT-TS) treated with pexidartinib versus placebo (ClinicalTrials.gov identifier NCT02371369). Although exciting clinical activity with CSF1R inhibition has been confirmed in dt-GCT, the safety profile of CSF1R-targeting compounds needs to be considered carefully in this non-life-threatening disease (see the next section for a detailed safety discussion).
Table 2

Clinical trials with CSF1/CSF1R inhibitors in combination with anti-tumor therapies (excluding cancer-immunotherapy doublets)

Class

Target

Compound

Combination partner

Clinical phase

Sponsor

Indication

ClinicalTrials.gov identifier

Status/Results

Reference

Small molecules

CSF1R (and cKIT, Flt3)

Pexidartinib

(PLX3397, PLX108-01)

Androgen-deprivation therapy plus external radiotherapy

1

Plexxikon/Daiichi Sankyo

Prostate cancer

NCT02472275

Ongoing

-

Paclitaxel

1

Plexxikon/Daiichi Sankyo

Solid tumors

NCT01525602

ORR: 4/23 (17%)

CBR: 14/23 (61%)

[35]

Eribulin

1/2

Plexxikon/Daiichi Sankyo

Breast cancer

NCT01596751

Ongoing

-

Temozolomide plus external radiotherapy

1/2

Plexxikon/Daiichi Sankyo

GBM

NCT01790503

Not yet reported

-

Vemurafenib

1

Plexxikon/Daiichi Sankyo

BRAF-mutated melanoma

NCT01826448

Terminated

-

PLX9486 (KIT inhibitor)

1/2

Plexxikon/Daiichi Sankyo

GIST

NCT02401815

Ongoing

-

Sirolimus

1/2

Plexxikon/Daiichi Sankyo

Advanced sarcomas, MPNST

NCT02584647

Ongoing, not yet reported

[73]

Monoclonal antibodies

CSF1R

Emactuzumab (RG7155)

Paclitaxel

1

Roche

Ovarian and breast cancer

NCT01494688

Not yet reported

-

CSF1R

Emactuzumab (RG7155)

Paclitaxel plus bevacizumab

2

Roche

Ovarian cancer

NCT02923739

Ongoing

-

CSF1

MCS110

Carboplatin plus gemcitabine

2

Novartis

TNBC

NCT02435680

Ongoing

-

CSF1

PD-0360324

Cyclophosphamide

2

Pfizer

Recurrent platinum-resistant epithelial ovarian, peritoneal, or fallopian tube cancer

NCT02948101

Ongoing

-

CBR clinical benefit rate, CSF1 colony-stimulating factor 1, CSF1R colony-stimulating factor 1 receptor, dt-GCT diffuse-type tenosynovial giant cell tumor, GBM glioblastoma, GIST gastrointestinal stromal tumor, MPNST malignant peripheral nerve sheath tumor, ORR objective response rate, TNBC triple-negative breast cancer

In addition to tumor shrinkage as a measure of efficacy, functional and symptomatic improvement is another important aspect to assessing clinical benefit in patients with dt-GCT. Patient-reported outcome measures could add evidence for superior clinical benefit of CSF1R inhibitors over surgery as the current mainstay of therapy. Test instruments such as the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) questionnaire, the Brief Pain Inventory (BPI), the worst pain numeric rating scale (NRS), 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 [24]

Clinical safety and tolerability of CSF1R inhibitors

Preliminary safety results from phase 1 and 2 studies have been reported for CSF1R inhibitor monotherapy in a variety of settings, including healthy subjects and patients with rheumatoid arthritis, cHL, or advanced solid tumors. 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 and peripheral edema, asthenia, pruritus, rash, nausea/vomiting, headache, dry skin, increased lacrimation, and decreased appetite [12, 17, 18, 22, 2630]. Increases in creatine kinase, lactate dehydrogenase, aspartate aminotransferase (AST), and alanine transaminase (ALT) were seen across studies [12, 17, 19, 22, 2527, 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 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]. 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.

However, there might be differences between CSF1R inhibition with mAbs and with small molecules. 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]. Potentially immune-related AEs have been described for mAbs [12], whereas serious liver injuries have not been reported. In contrast, enrolment into a phase 3 study with pexidartinib (NCT02371369) was recently suspended because two of 121 patients experienced non-fatal serious liver toxicity [33]. Whether 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]. 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.

In line with the overall favorable safety profile of CSF1R inhibitors, combination treatment studies have been initiated for both chemotherapies and targeted therapies or immunotherapies. For example, pexidartinib was tested together with paclitaxel in solid tumor patients, and no DLTs were reported [35]. As described in the next section, combinations with programmed cell death protein 1 (PD1) and programmed cell death-ligand 1 (PDL1) inhibitors are ongoing. As with most combination therapies, the promise of increased clinical activity is accompanied by the risk of additive toxicity and therefore requires careful assessment. However, the lack of significant overlapping toxicities of the single-agent AE profiles means these two classes of compounds are promising candidates for successful combination strategies.

Clinical combinations including CSF1R inhibitors

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. Notably, the attack of tumor cells via chemotherapy or irradiation induced an upregulation of tumor-derived CSF1 secretion followed by enhanced TAM infiltration that provided additional growth and survival factors for the tumor. A similar mechanism was described for anti-angiogenic therapy that resulted in enhanced supply of vascular endothelial growth factor (VEGF) by TAM. Hence, the combination of tumor-targeted or anti-angiogenic therapies and CSF1R inhibitors resulted in improved anti-tumoral activity. Another important link between TAM and cytotoxic CD8+ T cells was established using combinations with adoptive T-cell therapy or immune checkpoint inhibitors. In this context, TAM-derived suppressive cytokines such as IL-10 or the general T-cell suppressive functions of TAM provided the basis for increased tumor-inhibitory effects of CSF1R inhibitors combined with immunotherapies. On the basis of these results, multiple clinical trials combining various CSF1/CSF1R inhibitors with agents of diverse mechanisms of action were initiated. Examples include combinations with radiation and androgen-deprivation therapy in prostate cancer, radiation therapy and temozolomide in GBM, rapamycin in peripheral nerve sheet tumors, paclitaxel and eribulin in breast cancer, vemurafenib in melanoma, and KIT inhibitors in gastrointestinal stromal tumors (GISTs). Details and references are summarized in Table 2.
Table 3

Clinical trials with CSF1/CSF1R inhibitors in combination with cancer immunotherapy agents

Class

Target

Compound/Class

Combination partner

Clinical phase

Sponsor

Indication

ClinicalTrials.gov identifier

Status/Results

Reference

Small molecule

CSF1R (and cKIT, Flt3)

Pexidartinib (PLX3397, PLX108-01)

Pembrolizumab (anti-PD1 mAb)

1/2

Plexxikon/Daiichi Sankyo

Solid tumors, malignant melanoma

GIST, NSCLC, ovarian carcinoma, TNBC, SCCHN, UBC, pancreatic cancer, gastric carcinoma, leiomyosarcoma, cholangio carcinoma, CRC (MSS)

NCT02452424

Ongoing

[74]

Durvalumab (anti-PDL1 mAb)

1

Astra Zeneca

Pancreatic carcinoma, CRC

NCT02777710

Ongoing

-

CSF1R

ARRY-382

Pembrolizumab (anti-PD1 mAb)

1

Array BioPharma

Solid tumors, melanoma, NSCLC

NCT02880371

Ongoing

-

CSF1R

BLZ945

PDR001 (anti-PD1 mAb)

1/2

Novartis

Solid tumors

NCT02829723

Ongoing

-

Monoclonal antibody

CSF1R

Emactuzumab (RG7155)

Atezolizumab (anti-PDL1 mAb)

1

Roche

Solid tumors, TNBC, gastric cancer, soft tissue sarcoma, UBC, ovarian cancer, NSCLC, melanoma

NCT02323191

Ongoing

-

RG7876 (CD40 agonist mAb)

1

Roche

TNBC, gastric cancer, mesothelioma, CRC, melanoma, pancreatic cancer

NCT02760797

Ongoing

-

CSF1R

AMG820

Pembrolizumab (anti-PD1 mAb)

1

Amgen

Solid tumors

NCT02713529

Ongoing

-

CSF1R

Cabiralizumab (FPA008)

Nivolumab (anti-PD1 mAb)

1

FivePrime/BMS

Solid tumors, NSCLC, SCCHN, pancreatic cancer, ovarian cancer, RCC, GBM

NCT02526017

Ongoing

[75]

CSF1R

IMC-CS4 (LY3022855)

Durvalumab (anti-PDL1 mAb) or Tremelimumab (anti-CTLA4 mAb)

1

Eli Lilly

Solid tumors

NCT02718911

Ongoing

[76]

CSF1

MCS110

PDR001 (anti-PD1 mAb)

1/2

Novartis

Solid tumors, TNBC, pancreatic cancer, melanoma, endometrial cancer

NCT02807844

Ongoing

-

CSF1

PD-0360324

Avelumab (anti-PDL1 mAb)

1

Pfizer

Solid tumors

NCT02554812

Ongoing

-

CRC colorectal cancer, CSF1 colony-stimulating factor 1, CSF1R colony-stimulating factor 1 receptor, CTLA4 cytotoxic T-lymphocyte-associated protein 4, GBM glioblastoma, GIST gastrointestinal stromal tumor, mAb monoclonal antibody, MSS microsatellite stable, NSCLC non-small cell lung cancer, PD1 programmed cell death protein 1, PDL1 programmed cell death ligand 1, RCC renal cell carcinoma, SCCHN squamous cell carcinoma of the head and neck, TNBC triple-negative breast cancer, UBC urothelial bladder carcinoma

Clinical trials assessing the combination of CSF1R inhibitors with immune checkpoint inhibition clearly outnumber other ongoing combination efforts. This may be because immune checkpoint inhibitors have revolutionized therapeutic strategies in oncology, due to the durable clinical benefit experienced by a fraction of patients from enhancing systemic anti-tumor immunity. 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, and others [3742]. Despite the sustained and deep responses observed in some patients, the majority of cancer patients do not respond to these agents. The underlying primary and secondary resistance mechanisms are not well understood; however, evidence is increasing that overcoming the immunosuppressive TME is key to improving the clinical activity of cancer immunotherapy. It is well documented that TAM and other myeloid cells contribute to an immunosuppressive TME. 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 agents with CSF1R inhibitors have been initiated. Most of these trials are currently in the dose-finding phase or are evaluating safety and preliminary efficacy in expansion cohorts (Table 3). Clinical results are eagerly awaited, and investigators are aiming to establish superiority of the combination regimen over checkpoint inhibition monotherapy, with the ultimate goal of replacing the current standard of care in various tumor types.
Table 4

Clinical trials with CSF1R inhibitors for the treatment of dt-GCT

Class

Target

Compound

Clinical phase

Sponsor

Indication

ClinicalTrials.gov identifier

Status/ Results

Reference

Small molecules

CSF1R (and cKIT, Flt3)

Pexidartinib (PLX3397, PLX108-01)

1

Plexxikon

Solid tumors and extension for MEC, dt-GCT, GIST, ATC, metastatic solid tumors

NCT01004861

Ongoing

ORR: 12/23 (52%)

CBR: 19/23 (83%)

[22]

3

Plexxikon/Daiichi Sankyo

dt-GCT or GCT-TS

NCT02371369

Ongoing

-

Monoclonal antibodies

CSF1R

Emactuzumab (RG7155)

1

Roche

Solid tumors and dt-GCT

NCT01494688

ORR: 24/28 (86%)

CBR: 27/28 (96%

[12]

CSF1R

Cabiralizumab (FPA008)

1/2

FivePrime

dt-GCT

NCT02471716

Ongoing

-

CSF1

MCS110

2

Novartis

dt-GCT or GCT-TS

NCT01643850

Ongoing

ORR: 4/4 (100%)

[21]

ATC anaplastic thyroid cancer, CBR clinical benefit rate, CSF1 colony-stimulating factor 1, CSF1R colony-stimulating factor 1 receptor, dt-GCT diffuse-type tenosynovial giant cell tumor, GCT-TS giant cell tumor of the tendon sheath, GIST gastrointestinal stromal tumor, MEC mucoepidermoid carcinoma of the lung, ORR objective response rate

Apart from combining CSF1R inhibitors with PD1/PDL1 or CTLA4 antagonists, alternative strategies to further enhance anti-tumor efficacy of the host immune system are being investigated. Repolarization of the TME is being pursued by combining the CD40 agonist RO7009789 with the anti-CSF1R antibody emactuzumab in a phase 1 clinical trial (NCT02760797). 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 (NCT02923739).

Local tissue macrophage and disease specificity impacting CSF1R-directed treatment strategies

CSF1R-targeting agents exhibit a rather benign safety profile; however, to date, only modest clinical activity as monotherapy has been reported outside of CSF1-driven dt-GCT. Currently, important patient data sets for solid and hematological malignancies, especially those from ongoing combination trials, are still pending. The complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Therefore, a key question remaining to be answered in clinical studies is whether these agents provide benefit to all cancer patients by depleting CSF1R+ TAM, or whether certain patients and/or tumor types are more likely to respond to CSF1R inhibition. Evidence is increasing that the individual underlying tumor histology as well as organ site-specific features of CSF1R+ cells need to be considered.

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 defense [4648]. This supports the hypothesis that alveolar macrophages in healthy steady state are predominantly of the immunostimulatory M1 macrophage subtype. 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 (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. 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 phenotype, CSF1R inhibition may either a) reprogram an M2 TAM-dominated, immunosuppressive TME through depletion of CSF1R-dependent TAM or b) boost an ongoing anti-tumor response by increasing the M1/M2 TAM ratio in an M1 TAM-dominated TME. For both strategies, the choice of an appropriate combination partner will be key to reprogramming a tumor-promoting TME or boosting a pre-existing anti-tumor immune response. 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. As CD206 expression is high on alveolar macrophages, an elevated concentration of IL-4 in lung cancer patients may result in resistance to CSF1R inhibitors. Patient data on local IL-4 concentrations and the effect of CSF1R-targeting agents are not available yet.

The physiological steady state of intestinal macrophages in colon tissue is quite different from those in the lung. 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]. 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 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. 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 CSF1R-signaling dependency of macrophages at these different locations is still unclear. In addition to the location within the TME, the genetic stability of tumor cells may influence the general immune status of the TME. 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 CRC tumors, CSF1R-targeted therapies may still also be beneficial in this subset of CRC patients. 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 blockade in MSS CRC patients is able to control the invasiveness and metastasis remains to be investigated.

In contrast to monocyte-derived alveolar and intestinal macrophages, microglia of the central nervous system (CNS) are resident yolk sac-derived macrophages. 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 different origin than, for example, intestinal macrophages, the observed function of microglia seem to be similar to those of the M2 macrophage subtype described for intestinal macrophages in the healthy gut. 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, the local TME under anti-CSF1R treatment was dominated by tumor cell-derived GM-CSF and IFN-γ. Interestingly, this local cytokine milieu did not result in unresponsiveness of TAM to anti-CSF1R monotherapy treatment but rather in reprogramming of microglia from M2 into M1 TAM. A phase 2 clinical study assessing pexidartinib in GBM patients is currently ongoing (NCT01790503). In the aforementioned GBM in vivo model, long-term 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. Potential translational approaches to prevent or resolve resistance to CSF1R inhibition may consist of treatment schedules other than continuous administration of CSF1R inhibitors. Alternative schedules could, for example, pursue an initial anti-CSF1R-mediated debulking of M2 TAM followed by other treatment modalities to maintain or induce tumor immunity.

With several CSF1R-targeting therapies currently under evaluation in the clinic, we are still only beginning to understand which covariates impact on macrophage phenotypes and the respective role of CSF1R-mediated signaling in cancer. The aforementioned examples illustrate that the origin and the presence of a predominant macrophage phenotype in healthy tissue cannot alone predict pro- or anti-tumor effects of TAM during tumorigenesis. Furthermore, it is difficult to identify tumor types that might or might not benefit from CSF1R-targeted therapies without taking into account further sub-classification of tumors and their respective impact on the local TME. Both primary and disseminated tumor cells may induce a profound functional reprogramming of resident tissue macrophages by changing the local cytokine milieu. Only once the impact of organ-specific CSF1R blockade is better understood will a more precise selection of anti-CSF1R-containing treatment regimens and prediction of clinical benefit for patients be possible.

Conclusions

CSF1R inhibitors represent an exciting new class of immune-modulatory drugs. Scientific understanding of macrophage and CSF1R biology is evolving rapidly, and more data from clinical trials investigating CSF1R-directed therapies will become available shortly. Whereas clinical tolerability seems to have been established for this group of agents, it is increasingly clear that the organ site and tumor-type specifics of TAM will need to be considered for the selection of both the right patients population and the appropriate combination partner to achieve a meaningful clinical benefit for cancer patients.

Abbreviations

AE: 

Adverse event

ALT: 

Alanine aminotransferase

AST: 

Aspartate aminotransferase

ATC: 

Anaplastic thyroid cancer

BPI: 

Brief Pain Inventory

CBR: 

Clinical benefit rate

cHL: 

Classical Hodgkin lymphoma

CNS: 

Central nervous system

CRC: 

Colorectal cancer

CSF1: 

Colony-stimulating factor 1

CSF1R: 

Colony-stimulating factor 1 receptor

CTLA4: 

Cytotoxic T-lymphocyte-associated protein 4

DC: 

Dendritic cells

DLT: 

Dose-limiting toxicity

dt-GCT: 

Diffuse-type tenosynovial giant cell tumors

EMT: 

Epithelial to mesenchymal transition

FLT3: 

fms-like tyrosine kinase 3

GBM: 

Glioblastoma

GCT-TS: 

Giant cell tumor of the tendon sheath

GIST: 

Gastrointestinal stromal tumor

GM-CSF: 

Granulocyte-macrophage colony-stimulating factor

HLA-DR: 

Human leukocyte antigen-antigen D related

IDO: 

Indolamin-2,3-Dioxygenase

IFNγ: 

Interferon γ

IGF-1: 

Insulin-like growth factor 1

IHC: 

Immunohistochemistry

IL: 

Interleukin

iNOS: 

Inducible nitric oxide synthase

mAb: 

Monoclonal antibody

MCSF: 

Macrophage colony-stimulating factor

MDSC: 

Myeloid derived suppressor cells

MEC: 

Mucoepidermoid carcinoma of the lung

MPNST: 

Malignant peripheral nerve sheath tumor

MSI: 

Microsatellite instability

MSS: 

Microsatellite stable

MTD: 

Maximum tolerated dose

NRS: 

Numeric rating scale

NSCLC: 

Non-small cell lung cancer

ORR: 

Objective response rate

PD1: 

Programmed cell death protein 1

PDGFR: 

Platelet-derived growth factor receptor

PDL1: 

Programmed cell death-ligand 1

PFS: 

Progression-free survival

PPAR-γ: 

Peroxisome proliferator-activated receptor-γ

PROMIS: 

Patient-Reported Outcomes Measurement Information System

PVNS: 

Pigmented villonodular synovitis

RCC: 

Renal cell carcinoma

SCCHN: 

Squamous cell carcinoma of the head and neck

TAM: 

Tumor-associated macrophages

Th cells: 

T helper cells

TME: 

Tumor microenvironment

TNBC: 

Triple-negative breast cancer

TNFα: 

Tumor necrosis factor α

TRAIL: 

Tumor necrosis factor related apoptosis inducing ligand

UBC: 

Urothelial bladder carcinoma

VEGF: 

Vascular Endothelial Growth Factor

WOMAC: 

Western Ontario and McMasters Universities Osteoarthritis Index

Declarations

Acknowledgements

The authors thank Dr. Irina Klaman, pRED Roche Innovation Center Munich, for providing the immunohistochemistry analysis in Fig. 2 (Gomez-Roca et al. J Clin Oncol 2015;33). The authors thank Dr. William Pao, Dr. Friedrich Graf Finckenstein, and Dr. Monika Baehner for critical review of the manuscript.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Authors’ contributions

MW, CHR, MAC, WJ, AJ, and DR drafted and critically revised the manuscript. All authors read and approved the final manuscript.

Competing interests

M.W., C.H.R., M.A.C., W.J., A.J., and D.R. are employees of Roche Diagnostics GmbH. C.H.R., M.A.C., and D.R. are inventors of granted and pending patent applications relating to RG7155. M.W., C.H.R., M.A.C., W.J., and D.R. hold stock and stock options in F. Hoffman La Roche. The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

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Authors’ Affiliations

(1)
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Munich

References

  1. Lamagna C, Aurrand-Lions M, Imhof BA. Dual role of macrophages in tumor growth and angiogenesis. J Leukoc Biol. 2006;80:705–13.View ArticlePubMedGoogle Scholar
  2. Mills CD. M1 and M2 Macrophages: Oracles of Health and Disease. Crit Rev Immunol. 2012;32:463–88.View ArticlePubMedGoogle Scholar
  3. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41:49–61.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36:229–39.View ArticlePubMedGoogle Scholar
  5. Pedersen MB, Danielsen AV, Hamilton-Dutoit SJ, Bendix K, Norgaard P, Moller MB, Steiniche T, d’Amore F. High intratumoral macrophage content is an adverse prognostic feature in anaplastic large cell lymphoma. Histopathology. 2014;65:490–500.View ArticlePubMedGoogle Scholar
  6. Lenzo JC, Turner AL, Cook AD, Vlahos R, Anderson GP, Reynolds EC, Hamilton JA. Control of macrophage lineage populations by CSF-1 receptor and GM-CSF in homeostasis and inflammation. Immunol Cell Biol. 2012;90:429–40.View ArticlePubMedGoogle Scholar
  7. Stanley ER, Chitu V: CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol 2014, 6.Google Scholar
  8. Achkova D, Maher J. Role of the colony-stimulating factor (CSF)/CSF-1 receptor axis in cancer. Biochem Soc Trans. 2016;44:333–41.View ArticlePubMedGoogle Scholar
  9. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW, Wei YQ. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7:e50946.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Holmgaard RB, Zamarin D, Lesokhin A, Merghoub T, Wolchok JD. Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine. 2016;6:50–8.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016;7:12150.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Cassier PA, Italiano A, Gomez-Roca CA, Le Tourneau C, Toulmonde M, Cannarile MA, Ries C, Brillouet A, Muller C, Jegg AM, et al. CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. Lancet Oncol. 2015;16:949–56.View ArticlePubMedGoogle Scholar
  13. Ries CH, Cannarile MA, Hoves S, Benz J, Wartha K, Runza V, Rey-Giraud F, Pradel LP, Feuerhake F, Klaman I, et al. Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy. Cancer Cell. 2014;25:846–59.View ArticlePubMedGoogle Scholar
  14. Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, Cloughesy TF, Marimuthu A, Haidar S, Perry A, et al. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro Oncol. 2016;18:557–64.View ArticlePubMedGoogle Scholar
  15. Moskowitz CH, Younes A, de Vos S, Bociek RG, Gordon LI, Witzig TE, Gascoyne RD, West B, Nolop K, Steidl C: CSF1R Inhibition by PLX3397 in Patients with Relapsed or Refractory Hodgkin Lymphoma: Results From a Phase 2 Single Agent Clinical Trial. Blood 2012, 120.Google Scholar
  16. von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S, Aquino R, Kotoulek S, Khan I, de Boer C, Engert A: A Phase 1 Study Of JNJ-40346527, a Colony Stimulating Factor-1 Receptor (CSF-1R) Inhibitor, In Patients With Relapsed Or Refractory Hodgkin Lymphoma. Blood 2013, 122.Google Scholar
  17. Bendell JC, Tolcher AW, Jones SF, Beeram M, Infante JR, Larsen P, Rasor K, Garrus JE, Li JF, Cable PL, et al.: A phase 1 study of ARRY-382, an oral inhibitor of colony-stimulating factor-1 receptor (CSF1R), in patients with advanced or metastatic cancers. Molecular Cancer Therapeutics 2013, 12.Google Scholar
  18. Gomez-Roca CA, Cassier PA, Italiano A, Cannarile M, Ries C, Brillouet A, Mueller C, Jegg AM, Meneses-Lorente G, Baehner M, et al.: Phase I study of RG7155, a novel anti-CSF1R antibody, in patients with advanced/metastatic solid tumors. Journal of Clinical Oncology 2015, 33.Google Scholar
  19. Papadopoulos K, Gluck L, Martin LP, Olszanski AJ, Ngarmchamnanrith G, Rasmussen E, Amore B, Nagorsen D, Hill JS, Stephenson J: First-in-human study of AMG 820, a monoclonal anti-CSF-1R (c-fms) antibody, in patients (pts) with advanced solid tumors. Cancer Research 2016, 76.Google Scholar
  20. Blay JY, El Sayadi H, Thiesse P, Garret J, Ray-Coquard I. Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 2008;19:821–2.View ArticlePubMedGoogle Scholar
  21. Cheng EY ea: MCS110, an anti-CSF-1 antibody, for the treatment of pigmented villonodular synovitis (PVNS). In ISOLS/MSTS 2015 Annual Meeting, Abstract #11105, 2015.Google Scholar
  22. Tap WD, Wainberg ZA, Anthony SP, Ibrahim PN, Zhang C, Healey JH, Chmielowski B, Staddon AP, Cohn AL, Shapiro GI, et al. Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. N Engl J Med. 2015;373:428–37.View ArticlePubMedGoogle Scholar
  23. Gelhorn H, Tong S, Maclaine G, Healey JH, Bukata SV, Keedy VL, Anthony SP, Wagner AJ, Von Hoff DD, Singh AS, et al.: Patient-reported outcome instruments meaningful and relevant for tenosynovial giant cell tumor (TGCT): A qualitative study. Journal of Clinical Oncology 2015, 33.Google Scholar
  24. Gelhorn HL, Tong S, McQuarrie K, Vernon C, Hanlon J, Maclaine G, Lenderking W, Ye X, Speck RM, Lackman RD, et al. Patient-reported Symptoms of Tenosynovial Giant Cell Tumors. Clin Ther. 2016;38:778–93.View ArticlePubMedPubMed CentralGoogle Scholar
  25. von Tresckow B, Morschhauser F, Ribrag V, Topp MS, Chien C, Seetharam S, Aquino R, Kotoulek S, de Boer CJ, Engert A. An Open-Label, Multicenter, Phase I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory Hodgkin Lymphoma. Clin Cancer Res. 2015;21:1843–50.View ArticleGoogle Scholar
  26. Butowski NA, Colman H, De Groot JF, Omuro AMP, Nayak L, Cloughesy TF, Marlmuthu A, Perry A, Phillips JJ, West B, et al.: A phase 2 study of orally administered PLX3397 in patients with recurrent glioblastoma. Journal of Clinical Oncology 2014, 32.Google Scholar
  27. Hambleton J, Zhou L, Rogers S, van Marle S, van Iersel T, Zanghi J, Masteller E, Baker K, Wong B. A Phase 1 Study of FPA008, an Anti-Colony Stimulating Factor 1 Receptor (anti-CSF1R) Antibody in Healthy Volunteers and Subjects with Rheumatoid Arthritis (RA): Preliminary Results. Arthritis Rheum. 2014;66:S657.View ArticleGoogle Scholar
  28. Sadis S, Mukherjee A, Olson S, Dokmanovich M, Maher R, Cai C-H, Le V. Safety, Pharmacokinetics, And Pharmacodynamics Of PD-0360324, AHuman Monoclonal Antibody To Monocyte/Macrophage Colony Stimulating Factor, In Healthy Volunteers [abstract]. Arthritis Rheum. 2009;60 Suppl 10:408.Google Scholar
  29. Tap WD, Anthony SP, Chmielowski B, Staddon AP, Cohn AL, Shapiro G, Puzanov I, Kwak EL, Wagner AJ, Peterfy C, et al.: A pilot study of PLX3397, a selective colony-stimulating factor 1 receptor (CSF1R) kinase inhibitor, in pigmented villonodular synovitis (PVNS). Journal of Clinical Oncology 2014, 32.Google Scholar
  30. Zhou L, Sikorski R, Rogers S, Costin S, Korkosz M, Jaraczewska-Baumann M, Eva P, Rojkovich B, Bartalos J, Masteller E, et al.: A Phase 1 Study of FPA008, an Anti-Colony Stimulating Factor 1 Receptor (anti-CSF1R) Antibody in Patients (pts) with Rheumatoid Arthritis (RA): Preliminary Results. Arthritis & Rheumatology 2015, 67.Google Scholar
  31. Genovese MC, Hsia E, Belkowski SM, Chien C, Masterson T, Thurmond RL, Manthey CL, Yan XY, Ge TT, Franks C, Greenspan A. Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy. J Rheumatol. 2015;42:1752–60.View ArticlePubMedGoogle Scholar
  32. Radi ZA, Koza-Taylor PH, Bell RR, Obert LA, Runnels HA, Beebe JS, Lawton MP, Sadis S. Increased Serum Enzyme Levels Associated with Kupffer Cell Reduction with No Signs of Hepatic or Skeletal Muscle Injury. Am J Pathol. 2011;179:240–7.View ArticlePubMedPubMed CentralGoogle Scholar
  33. ENLIVEN Phase 3 Study of Pexidartinib in Tenosynovial Giant Cell Tumor (TGCT) Will Continue to Completion Following Enrollment Discontinuation [media release]. Tokyo: Daiichi Sankyo Company Ltd; 21 October 2016. [http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006538.html]
  34. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503.View ArticlePubMedGoogle Scholar
  35. Rugo HS, Sharma N, Reebel L, Rodal MB, Peck A, West BL, Marimuthu A, Karlin DA, Dowlati A, Le MH, et al.: Phase Ib Study of Plx3397, a Csf1r Inhibitor, and Paclitaxel in Patients with Advanced Solid Tumors. Annals of Oncology 2014, 25.Google Scholar
  36. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.View ArticlePubMedPubMed CentralGoogle Scholar
  37. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.View ArticlePubMedGoogle Scholar
  38. Ferris RL, Blumenschein Jr G, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375:1856–67.View ArticlePubMedGoogle Scholar
  39. Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540–50.View ArticlePubMedGoogle Scholar
  40. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373:1803–13.View ArticlePubMedGoogle Scholar
  41. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.View ArticlePubMedGoogle Scholar
  42. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387:1909–20.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Mok S, Koya RC, Tsui C, Xu J, Robert L, Wu L, Graeber TG, West BL, Bollag G, Ribas A. Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. Cancer Res. 2014;74:153–61.View ArticlePubMedGoogle Scholar
  44. Guilliams M, De Kleer I, Henri S, Post S, Vanhoutte L, De Prijck S, Deswarte K, Malissen B, Hammad H, Lambrecht BN. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med. 2013;210:1977–92.View ArticlePubMedPubMed CentralGoogle Scholar
  45. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008;8:533–44.View ArticlePubMedGoogle Scholar
  46. Kuroki Y, Takahashi M, Nishitani C. Pulmonary collectins in innate immunity of the lung. Cell Microbiol. 2007;9:1871–9.View ArticlePubMedGoogle Scholar
  47. Nakamura A, Ebina-Shibuya R, Itoh-Nakadai A, Muto A, Shima H, Saigusa D, Aoki J, Ebina M, Nukiwa T, Igarashi K. Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function. J Exp Med. 2013;210:2191–204.View ArticlePubMedPubMed CentralGoogle Scholar
  48. Schneider C, Nobs SP, Kurrer M, Rehrauer H, Thiele C, Kopf M. Induction of the nuclear receptor PPAR-gamma by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014;15:1026–37.View ArticlePubMedGoogle Scholar
  49. Almatroodi SA, McDonald CF, Darby IA, Pouniotis DS. Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC. Cancer Microenviron. 2016;9:1–11.View ArticlePubMedGoogle Scholar
  50. Pradel LP, Ooi CH, Romagnoli S, Cannarile MA, Sade H, Ruttinger D, Ries CH. Macrophage Susceptibility to Emactuzumab (RG7155) Treatment. Mol Cancer Ther. 2016;15:3077–86.View ArticlePubMedGoogle Scholar
  51. Bain CC, Bravo-Blas A, Scott CL, Gomez Perdiguero E, Geissmann F, Henri S, Malissen B, Osborne LC, Artis D, Mowat AM. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nat Immunol. 2014;15:929–37.View ArticlePubMedPubMed CentralGoogle Scholar
  52. Amit I, Winter DR, Jung S. The role of the local environment and epigenetics in shaping macrophage identity and their effect on tissue homeostasis. Nat Immunol. 2016;17:18–25.View ArticlePubMedGoogle Scholar
  53. Kaler P, Augenlicht L, Klampfer L. Activating mutations in beta-catenin in colon cancer cells alter their interaction with macrophages; the role of snail. PLoS One. 2012;7:e45462.View ArticlePubMedPubMed CentralGoogle Scholar
  54. Kruse J, von Bernstorff W, Evert K, Albers N, Hadlich S, Hagemann S, Gunther C, van Rooijen N, Heidecke CD, Partecke LI. Macrophages promote tumour growth and liver metastasis in an orthotopic syngeneic mouse model of colon cancer. Int J Colorectal Dis. 2013;28:1337–49.View ArticlePubMedGoogle Scholar
  55. MacDonald KP, Palmer JS, Cronau S, Seppanen E, Olver S, Raffelt NC, Kuns R, Pettit AR, Clouston A, Wainwright B, et al. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Blood. 2010;116:3955–63.View ArticlePubMedGoogle Scholar
  56. Owusu BY, Vaid M, Kaler P, Klampfer L. Prognostic and Predictive Significance of Stromal Fibroblasts and Macrophages in Colon Cancer. Biomark Cancer. 2015;7:29–37.PubMedPubMed CentralGoogle Scholar
  57. Erreni M, Mantovani A, Allavena P. Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Cancer Microenviron. 2011;4:141–54.View ArticlePubMedGoogle Scholar
  58. Kim CG, Ahn JB, Jung M, Beom SH, Kim C, Kim JH, Heo SJ, Park HS, Kim JH, Kim NK, et al. Effects of microsatellite instability on recurrence patterns and outcomes in colorectal cancers. Br J Cancer. 2016;115:25–33.View ArticlePubMedPubMed CentralGoogle Scholar
  59. Xiao Y, Freeman GJ. The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov. 2015;5:16–8.View ArticlePubMedPubMed CentralGoogle Scholar
  60. Mlecnik B, Bindea G, Angell HK, Maby P, Angelova M, Tougeron D, Church SE, Lafontaine L, Fischer M, Fredriksen T, et al. Integrative Analyses of Colorectal Cancer Show Immunoscore Is a Stronger Predictor of Patient Survival Than Microsatellite Instability. Immunity. 2016;44:698–711.View ArticlePubMedGoogle Scholar
  61. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, Kaiser EA, Snyder LA, Pollard JW. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222–5.View ArticlePubMedPubMed CentralGoogle Scholar
  62. Techasen A, Loilome W, Namwat N, Dokduang H, Jongthawin J, Yongvanit P. Cytokines released from activated human macrophages induce epithelial mesenchymal transition markers of cholangiocarcinoma cells. Asian Pac J Cancer Prev. 2012;13(Suppl):115–8.PubMedGoogle Scholar
  63. Afik R, Zigmond E, Vugman M, Klepfish M, Shimshoni E, Pasmanik-Chor M, Shenoy A, Bassat E, Halpern Z, Geiger T, et al. Tumor macrophages are pivotal constructors of tumor collagenous matrix. J Exp Med. 2016;213:2315–31.View ArticlePubMedPubMed CentralGoogle Scholar
  64. Fourgeaud L, Traves PG, Tufail Y, Leal-Bailey H, Lew ED, Burrola PG, Callaway P, Zagorska A, Rothlin CV, Nimmerjahn A, Lemke G. TAM receptors regulate multiple features of microglial physiology. Nature. 2016;532:240–4.View ArticlePubMedPubMed CentralGoogle Scholar
  65. Ransohoff RM, Cardona AE. The myeloid cells of the central nervous system parenchyma. Nature. 2010;468:253–62.View ArticlePubMedGoogle Scholar
  66. Erblich B, Zhu LY, Etgen AM, Dobrenis K, Pollard JW: Absence of Colony Stimulation Factor-1 Receptor Results in Loss of Microglia, Disrupted Brain Development and Olfactory Deficits. Plos One 2011, 6.Google Scholar
  67. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al. Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive Macrophages. Science. 2010;330:841–5.View ArticlePubMedPubMed CentralGoogle Scholar
  68. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.View ArticlePubMedPubMed CentralGoogle Scholar
  69. Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron. 2014;82:380–97.View ArticlePubMedPubMed CentralGoogle Scholar
  70. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 2006;8:261–79.View ArticlePubMedPubMed CentralGoogle Scholar
  71. Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216:15–24.View ArticlePubMedGoogle Scholar
  72. Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, Holland EC, Sutton JC, Joyce JA. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2016;352:aad3018.View ArticlePubMedPubMed CentralGoogle Scholar
  73. Gulam Abbas Manji PP, Shing Mirn Lee, Nanette Matos, Edward Bentlyewski, Brian Andrew Van Tine, Khanh Tu Do, Suzanne George, Gary K. Schwartz: Phase 1/2 study of combination therapy with pexidartinib and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors. In J Clin Oncol 34, 2016 (suppl; abstr TPS11070); 2016.Google Scholar
  74. Hu-Lieskovan S, Patnaik A, Eisenberg P, Sachdev J, Weise A, Kaufman DR, Aromin I, West BL, Tong S, Ribas A. Phase 1/2a study of double immune suppression blockade by combining a CSF1R inhibitor (pexidartinib/PLX3397) with an anti PD-1 antibody (pembrolizumab) to treat advanced melanoma and other solid tumors. Ann Oncol. 2015;26:7–7.View ArticleGoogle Scholar
  75. Brahmer J, Rasco D, Chen MJ, Masteller E, Qazi I, Rogers S, Sankar N, Sikorski R, Hambleton J, Hodi FS: A phase 1a/1b study of FPA008 in combination with nivolumab in patients with selected advanced cancers. Cancer Immunology Research 2016, 4.Google Scholar
  76. Bauer T. Phase Ia/Ib trial investigating the CSF-1R inhibitor LY3022855 in combination with durvalumab (MEDI4736) or tremelimumab in patients with advanced solid malignancies. J ImmunoTher Cancer. 2016;4 Suppl 1:P137.Google Scholar

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