Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

Priceman, Saul J.; Sung, James L.; Shaposhnik, Zory; Burton, Jeremy B.; Torres-Collado, Antoni X.; Moughon, Diana; Johnson, Mai; Lusis, Aldons J.; Cohen, Donald A.; Iruela‐Arispe, M. Luisa; Wu, Lily

doi:10.1182/blood-2009-08-237412

Cited by 314 publications

(304 citation statements)

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“…3A). These observations are consistent with other reports 14,16,18,27 and suggest that melanoma and lung tumor cells frequently produce high levels of CSF-1. In addition to CSF-1, CSF-1R expression was frequently detected in both melanoma and lung tumors.…”

Section: Csf-1/csf-1r Signaling Blockade Reduces the Suppressive Capasupporting

confidence: 93%

“…14,15 It has been demonstrated that CSF-1 is involved in myeloid infiltration of tumors leading to increased tumor progression and angiogenesis. 13,14,[16][17][18] Targeting of CSF-1R has therefore emerged as a strategy to limit attraction of MDSCs or block their tumor-promoting functions. 19,20 In preclinical studies, therapeutic antibodies and small-molecule inhibitors directed against CSF-1R have been reported to inhibit the immunosuppressive tumor microenvironment and facilitate immune responses to cancer.…”

Section: Introductionmentioning

confidence: 99%

“…19,20 In preclinical studies, therapeutic antibodies and small-molecule inhibitors directed against CSF-1R have been reported to inhibit the immunosuppressive tumor microenvironment and facilitate immune responses to cancer. 16,[21][22][23][24][25] This pathway has led to the development of various anti-CSF-1R antibodies and small molecule inhibitors as a single agent and in combination with other therapeutic modalities for the treatment of cancer patients. 26 In the current study, we evaluate the mechanism by which blockade of CSF-1/CSF-1R signaling inhibits MDSCs by exploring both murine and human systems.…”

Section: Introductionmentioning

confidence: 99%

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Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy.Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number and function of tumor-infiltrating immunosuppressive myeloid cells. In addition, our findings suggest that reprogramming myeloid responses may be a key in effectively enhancing cancer immunotherapy, offering several new potential combination therapies for future clinical testing. More importantly for clinical trial design, the timing of these interventions is critical to achieving improved tumor protection.

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Section: Csf-1/csf-1r Signaling Blockade Reduces the Suppressive Capasupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

et al. 2016

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“…For example, TAM depletion with clodronate liposomes synergizes with sorafinib in human hepatocellular carcinoma xenograft models [141] and with the anti-VEGFR2 antibody, DC101, in subcutaneous colon tumors [142] to reduce tumor growth. Synergy also occurs when combining a CSF1R inhibitor with DC101 in another transplantable model [143].…”

Section: Immune Cell Function Following Vascular-targeting Agentsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

121

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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“…12 More recently, the preclinical CSF1R inhibitor GW2580 (2) (Figure 1) inhibited tumor metastasis and angiogenesis in mouse tumor xenograft experiments. 13 JNJ-28312141 (3), a dual inhibitor of CSF1R and FLT3, also demonstrated suppression of solid tumor growth and preservation of bone in preclinical models. 14 CSF1R is also implicated in inflammatory arthritis, as M-CSF, together with RANK ligand, is required for osteoclastogenesis.…”

mentioning

confidence: 99%

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

Liu¹,

Campbell²,

Holladay³

et al. 2012

ACS Med. Chem. Lett.

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A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the α-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collageninduced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate. KEYWORDS: platelet-derived growth factor receptor (PDGFR)-family kinases, feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), colony-stimulating factor-1 receptor (CSF1R) inhibitor, acute myeloid leukemia (AML), cancer bone metastasis, inflammatory arthritis, AC710 R eceptor tyrosine kinases (RTKs) are a subfamily of protein kinases that critically regulate the processes of normal cell signaling and many pathological conditions. 1 A class of RTKs known as the platelet-derived growth factor receptor (PDGFR) family, 2,3 which includes colony-stimulating factor-1 receptor (CSF1R, also known as FMS), feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3), stem cell factor receptor (KIT), and PDGFR α and β, has been implicated in various proliferative and inflammatory diseases. 4 We were particularly interested in two members of this family of kinases. Activating internal tandem duplication (ITD) mutations in FLT3 are detected in approximately 30% of acute myeloid leukemia (AML) patients and are associated with poor prognosis. 5 AC220 (1, quizartinib) (Figure 1), a potent FLT3 inhibitor from this laboratory, 6 has demonstrated convincing clinical activity in FLT3-ITD+ AML patients. 7 CSF1R is the exclusive receptor for the macrophage colonystimulating factor (M-CSF or CSF-1). 8 Activation of CSF1R leads to the proliferation, survival, motility, and differentiation of cells of the monocyte/macrophage lineage and hence plays a role in normal tissue development and immune defense. 9,10 Activation of CSF1R also leads to the proliferation and differentiation of osteoclast precursors and therefore mediates the process of bone resorption. 11 It has been shown that M-CSF is one of several cytokines implicated in the recruitment of tumor-associated macrophages (TAMs) that contribute to tumor angiogenesis and tumor progression to metastasis. 12 More recently, the preclinical CSF1R inhibitor GW2580 (2) (Figure 1) inhibited tumor metastasis and angiogenesis in mouse tumor xenograft experiments. 13 JNJ-28312141 (3), a dual inhibitor of CSF1R and FLT3, also demonstrated suppression of solid tumor growth and preservation of bone in preclinical models. 14 CSF1R is also implicated in inflammatory arthritis, as M-CSF, together with RANK ligand, is required for osteoclastogenesis. 15 Elevated M-CFS signaling leads to increased osteoclast activity and bone loss attending arthritis, 16 a...

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Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy

Cited by 314 publications

References 46 publications

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases

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