CSF-1/CSF-1R targeting agents in clinical development for cancer therapy
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 [1]. Accordingly, the presence of macrophage infiltration ranges from either association with poor or favorable prognostic outcome depending on the specific cancer type [2]. Colony-stimulating factor-1 (CSF-1) controls survival and differentiation of macrophages [3]. 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 [4•], to repolarization of macrophages toward their tumor killing phenotype within the tumor using the CD40 agonistic antibody, CP-870,893 [5], 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 expression 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].
In this review we focus on the most recent learnings from the clinic on efficacy and tolerability of CSF-1R inhibitors in cancer patients. Since successful clinical development of this tumor microenvironment targeting approach is, in our view, dependent on effective combination strategies, we highlight the combinations currently pursued in the clinic as well as efficacious combinations with CSF-1/CSF-1R inhibitors in mouse tumor models.
Section snippets
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
Can mouse TAM and in vitro differentiated human macrophages predict the TAM phenotypes in cancer patients?
Till date, most of the data on TAM and other myeloid cell populations derive from transplanted syngeneic (or even xenograft) tumor models or oncogene driven tumors, not reflecting the high TAM heterogeneity in human patients. Unlike other immune cells relevant for cancer immunotherapy such as T cells, which express defined marker sets to describe different subtypes, macrophage populations shift expression of multiple markers upon activation leading to unclear, often confusing nomenclature and
Pre-clinical combination studies using CSF-1/CSF-1R inhibitors
In preclinical models, the CSF-1R pathway can be blocked by using either small molecule kinase inhibitors (GW2580 [30], PLX3397 [31], Ki20227 [32], BLZ945 [33] and CYC11645 [34]), antibody-mediated inhibition of CSF-1 using 5A1 [35] or anti-CSF-1R antibodies such as AFS98 [36], M279 [37] and 2G2 [6••] (Figure 1B). However, CSF-1R blockade alone has only marginal therapeutic benefit resulting at best in a delay of tumor growth. Therefore, various combination partners for CSF-1R-mediated TAM
Future direction and conclusion
Results of the clinical combination treatment of CSF-1R inhibitors and other immunotherapies are currently pending. Overall, on-target toxicities, i.e. depletion of macrophages outside the tumor remain a potential challenge even though early clinical data for various CSF1R inhibitors suggest good tolerability. A better understanding of the degree of macrophage infiltration as well as of the characteristics of various macrophage subsets in individual cancer patients is currently lacking although
Conflict of interest
C.H.R., S.H., M.A.C. and D.R. are employees of Roche Diagnostics GmbH and are inventors of granted and pending patent applications relating to RG7155. C.H.R., M.A.C. and D.R. hold stock and stock options in F. Hoffman La Roche.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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