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Clinical evaluation of colony-stimulating factor 1 receptor inhibitors
1Syndax Pharmaceuticals, Inc., Waltham, MA, USA.
Abstract:
Signaling through colony-stimulating factor 1 receptor (CSF1R) regulates the development, differentiation, and activation of mononuclear phagocytic cells. Inhibition of this pathway provides an opportunity for therapeutic intervention in diseases in which these cells play a pathogenic role, including cancers, inflammation, fibrosis, and others. Multiple monoclonal antibodies and small molecule inhibitors targeting CSF1R or its known ligands CSF1 and IL-34 have been clinically tested and are generally well tolerated with side effects associated with on-target macrophage inhibition or depletion. To date, clinical activity of CSF1R inhibitors has been primarily observed in diffuse-type tenosynovial giant cell tumors, a disease characterized by genetic alterations in CSF1 leading to dysregulated CSF1R signaling. Expanded development into novel indications such as chronic graft vs host disease may provide new opportunities to further explore areas where a role for CSF1R dependent monocytes and macrophages has been established. This review presents key findings from the clinical development of 12 CSF1/CSF1R targeted therapies as monotherapy or in combination with immune checkpoint inhibitors and chemotherapy.
Insights
Targeting colony-stimulating factor 1 receptor (CSF1R) with inhibitors shows promise for treating cancers and inflammatory diseases by modulating mononuclear phagocytes. Clinical development of 12 CSF1/CSF1R therapies is reviewed.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Colony-stimulating factor 1 receptor (CSF1R) signaling is crucial for mononuclear phagocyte development and function.
- Dysregulated CSF1R signaling contributes to various diseases, including cancers, inflammation, and fibrosis.
- CSF1R inhibitors offer a therapeutic strategy by targeting these pathogenic cells.
Purpose of the Study:
- To review the clinical development of CSF1/CSF1R targeted therapies.
- To assess the efficacy and safety of these inhibitors in various disease contexts.
- To explore potential new indications for CSF1R inhibition.
Main Methods:
- Review of clinical trial data for 12 CSF1/CSF1R targeted therapies.
- Analysis of monotherapy and combination treatment outcomes.
- Evaluation of side effects related to macrophage inhibition or depletion.
Main Results:
- CSF1R inhibitors are generally well-tolerated, with side effects linked to on-target macrophage modulation.
- Clinical activity is most prominent in diffuse-type tenosynovial giant cell tumors due to CSF1 alterations.
- Expanded development is underway for conditions like chronic graft vs host disease.
Conclusions:
- CSF1R inhibitors represent a viable therapeutic class for diseases involving mononuclear phagocytes.
- Further exploration in new indications like chronic graft vs host disease is warranted.
- Combination therapies with immune checkpoint inhibitors and chemotherapy are being investigated.
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