CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

Ries, Carola H.; Hoves, Sabine; Cannarile, Michael A.; Rüttinger, Dominik

doi:10.1016/j.coph.2015.05.008

Cited by 105 publications

(94 citation statements)

References 51 publications

(76 reference statements)

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“…Although inhibiting the CSF-1/ CSF-1R axis alone constrains tumor growth in preclinical models by partially decreasing TAMs and encouraging T-cell infiltration (12)(13)(14)(15)(16), it has often proven insufficient to clear tumors. Pairing CSF-1R blockade with chemotherapeutic agents or checkpoint inhibitors has enhanced efficacy of the monotherapy activity of CSF-1R (17).…”

Section: Introductionmentioning

confidence: 99%

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

Wiehagen

Girgis

Yamada

et al. 2017

Cancer Immunology Research

126

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Efficacious antitumor immune responses must overcome multiple suppressive mechanisms in the tumor microenvironment to control cancer progression. In this study, we demonstrate that dual targeting of suppressive myeloid populations by inhibiting CSF-1/CSF-1R signaling and activation of antigen-presenting cells with agonist anti-CD40 treatment confers superior antitumor efficacy and increased survival compared with monotherapy treatment in preclinical tumor models. Concurrent CSF-1R blockade and CD40 agonism lead to profound changes in the composition of immune infiltrates, causing an overall decrease in immunosuppressive cells and a shift toward a more inflammatory milieu. Anti-CD40/anti-CSF-1R-treated tumors contain decreased tumor-associated macrophages and Foxp3 þ regulatory T cells. This combination approach increases maturation and differentiation of proinflammatory macrophages and dendritic cells and also drives potent priming of effector T cells in draining lymph nodes. As a result, tumor-infiltrating effector T cells exhibit improved responses to tumor antigen rechallenge. These studies show that combining therapeutic approaches may simultaneously remove inhibitory immune populations and sustain endogenous antitumor immune responses to successfully impair cancer progression.

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Section: Introductionmentioning

confidence: 99%

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

Wiehagen

Girgis

Yamada

et al. 2017

Cancer Immunology Research

126

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“…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. We find that recruitment of MDSCs to tumors is regulated by CSF-1/CSF-1R signaling, and that inhibition of CSF-1/CSF-1R signaling with blocking antibodies alleviates immune suppression not only by decreasing the number of MDSCs, but also by reprogramming MDSCs to facilitate antigen presentation and augment T-cell activation within the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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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“…In human diseases, macrophages have been mainly seen as either pro-inflammatory or anti-inflammatory [6][7][8]. As a consequence, strategies targeting macrophages have been designed along this bipolar model [8,9] if not targeting macrophages as a whole [1,10]. In light of recent findings in tissue macrophages [11 ,12 ], concerning the ontogeny of macrophages [13][14][15][16][17][18], but also their activation by stresssignals [19,20,21 ,22 ], therapeutic approaches targeting macrophages need to be revisited.…”

Section: Introductionmentioning

confidence: 99%

Reprogramming of macrophages — new opportunities for therapeutic targeting

Schultze

2016

Current Opinion in Pharmacology

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CSF-1/CSF-1R targeting agents in clinical development for cancer therapy

Cited by 105 publications

References 51 publications

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity

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

Reprogramming of macrophages — new opportunities for therapeutic targeting

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