br Acknowledgements These studies were supported by a
Acknowledgements These studies were supported by a research grant from the NIH (R01 AR065594) to C. Putterman.
Introduction Macrophages integrate and adapt to their locally encountered cytokine and chemokine milieu. In tumors characterized by an unresolving inflammation, the tumor cell-killing macrophages convert into tumor-supporting macrophages providing not only growth and pro-angiogenic factors, but also promoting an immunosuppressive environment . Accordingly, the presence of macrophage infiltration ranges from either association with poor or favorable prognostic outcome depending on the specific cancer type . Colony-stimulating factor-1 (CSF-1) controls survival and differentiation of macrophages . Current clinical approaches for therapeutic targeting of tumor-associated macrophages (TAMs) in oncology range from induction of apoptosis in monocytes via the chemotherapeutic agent trabectedin , to repolarization of macrophages toward their tumor killing phenotype within the tumor using the CD40 agonistic antibody, CP-870,893 , and inhibition of TAM survival by CSF-1R blockade [6••, 7]. The modulation of TAM survival/activation by targeting the CSF-1/CSF-1R axis is particularly attractive as CSF-1 is highly expressed by several tumor types and both the CSF-1 UNC0638 and the intra-tumoral presence of CSF-1R+ macrophages have been shown to correlate with poor survival in various solid tumors and hematological malignancies [2, 8]. Reviews with a focus on general therapeutic strategies to exploit or target macrophages have been published recently [9, 10, 11].
Clinical development of CSF-1/CSF-1R inhibitors Currently, at least nine clinical stage oncology programs developing CSF-1/CSF-1R inhibitors are underway (Table 1 and Figure 1A). However, the availability of clinical data, on both safety and clinical activity, is still limited. Objective responses for single agent treatment have been reported in up to 83% of patients with diffuse type giant cell tumor (dt-GCT or PVNS) for RG7155 (Emactuzumab), a humanized anti-CSF-1R IgG1 monoclonal antibody and PLX3397, an oral tyrosine kinase inhibitor of CSF-1R, cKIT, mutant Flt3 and PDGFRβ [6••, 12, 13, 14, 15]. PVNS is an orphan disease with high unmet medical need, characterized by an overexpression of CSF-1, usually caused by a chromosomal translocation involving the CSF-1 gene. Thus, PVNS serves as a “model disease” for agents interfering with CSF-1R and its ligands. For other solid tumors and recurrent GBM, early data on clinical activity are available for PLX3397, however no objective responses were reported [16, 17]. In 2012, Moskowitz presented an overall response rate of 5% in a heavily pretreated population of patients suffering from Hodgkin lymphoma when treated with single agent PLX3397 . Another tyrosine kinase inhibitor, JNJ-40346527, was also investigated in relapsed or refractory Hodgkin lymphoma. In this phase 1/2 study, one patient out of 21 showed complete remission as best overall response and 11 patients experienced disease stabilization . Both RG7155 and PLX3397 have induced comparable pharmacodynamic changes including a decrease in CD14+CD16+ positive peripheral monocytes and an increase in systemic CSF-1, the latter being more prominent for RG7155. For RG7155, analysis of paired tumor specimens revealed a profound reduction of TAM and an increase of the CD8/CD4T cell ratio in the tumor across various solid malignancies . Furthermore, increases in short lived enzymes such as AST and LDH were observed, likely as the consequence of decreased physiologic clearance of these enzymes following depletion of CSF-1R positive Kupffer cells of the liver [19, 20]. Frequent adverse events observed in patients treated with a selective antibody as well as less selective small molecule inhibitors and hence likely attributable to the CSF-1R pathway inhibition, include fatigue, asthenia, facial edema (including periorbital edema) and skin-related adverse events such as rash and pruritus. The vast majority of events were of grade 1/2 severity [12, 16, 17, 18].