Interest Builds in CSF1R for Targeting Tumor Microenvironment

A growing appreciation of the role of the tumor microenvironment in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target components of this supportive niche as opposed to the tumor itself.

As part of their immunosurveillance duties, immune cells form part of this microenvironment, and yet cancer cells have devised means to downplay their tumoricidal capabilities.¹ Designing drugs that can overcome these immunosuppressive mechanisms and switch the infiltrating immune cells back on poses an attractive therapeutic strategy.

In this context, targeting colony stimulating factor 1 receptor (CSF1R) may offer just such a means of controlling the tumor-associated macrophages (TAMs) that are found in the microenvironment. Several CSF1R inhibitors have been developed that are designed to reprogram macrophages from an immunosuppressive, anti-inflammatory phenotype and kick them back to life in their role as the first line of defense in the antitumor immune response.

Macrophages in Microenvironment

As a class, CSF1R inhibitors have proved mostly disappointing in early clinical trials when used as monotherapy. Researchers believe their true potential can be tapped by combining them with other anticancer drugs, such as immune checkpoint inhibitors. Combinations are being explored in several early-stage clinical trials.Tumors do not grow in isolation. They are surrounded by a network of normal cells, tissues, and vasculature that are collectively dubbed the tumor microenvironment. In recent years, it has become increasingly evident that the microenvironment is not merely a bystander in tumor development and progression, that it can be corrupted by the tumor to become an active collaborator (FIGURE 1).¹

Figure 1. Cancer Hallmarks in the Microenvironment¹

Among the components that make up the tumor microenvironment are many types of immune cells. These cells are part of the antitumor immune response and can help to control tumor growth. However, tumors have developed mechanisms of immunosuppression that blunt the immune cells’ activity and foster tumor growth.

A particularly prominent type of tumorinfiltrating immune cell is the macrophage. The cells in this group are responsible for creating the characteristic high level of inflammation in the tumor microenvironment. They are part of the mononuclear phagocyte system, a network of cells that share common properties, including the ability to digest foreign substances and old or damaged cells, and form an important part of the innate immune response.

Macrophages are a very plastic cell type that undergoes changes in phenotype and function in response to cues from their local environment. Although it is widely believed that a continuum of phenotypes likely exists, macrophages switch between 2 main phenotypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). The former are proinflammatory and immunostimulatory, while the latter are anti-inflammatory and immunosuppressive (FIGURE 2).²

Figure 2. Factors Affecting Immune Response

Central Role of CSF1R

Tumors capitalize on this phenotypic switch by secreting cytokines into the tumor microenvironment that foster the development of M2-like TAMs that promote tumor growth by providing growth factors and proangiogenic molecules and suppressing the antitumor immune response.^1,3,4The cells that make up the mononuclear phagocyte system are governed by a number of signaling pathways that translate external environmental cues into cellular activity. Particularly crucial, especially in macrophages, is CSF1R-mediated signaling.

CSF1R is a tyrosine kinase receptor that spans the cell membrane and is activated by the binding of 2 known cytokine ligands: colony stimulating factor 1 (CSF1) and IL-34. Upon ligand binding, 2 receptor molecules pair up and several key tyrosine residues on the part of the receptor that protrudes into the cell are phosphorylated. This acts as a binding platform for downstream-signaling molecules and activates several signaling cascades, including the PI3K/AKT, mitogen-activated protein kinase, and SRC pathways.

These pathways ultimately sustain the growth, proliferation, survival, differentiation, and function of macrophages and other myeloid cells, including myeloid-derived suppressor cells, although much less is understood about the contribution of the signaling networks to the function of these other cell types.

The CSF1R pathway also may play an important role in macrophage polarization; that is, the M1/M2 dichotomy, which has important implications for the development of a variety of pathological conditions.

In the context of cancer, evidence suggests that the CSF1R signaling pathway promotes recruitment of M2 macrophages to the tumor microenvironment. This type of TAM facilitates the development of the tumor by secreting proangiogenic and growth factors and suppressing T-cell effector function by releasing immunosuppressive cytokines. Several tumor types have been shown to overexpress the CSF1 ligand; this expression and the presence of CSF1R-positive TAMs in the tumor microenvironment correlate with poor survival.

Reproducing TAMs Through CSF1R Inhibition

Diffuse-type tenosynovial giant cell tumor (dt-TGCT), a rare benign tumor that affects the large joints, exemplifies the protumoral role of the CSF1R pathway. These tumors are characterized by overexpression of CSF1 due to chromosomal translocations in the gene (CSF1) that encodes this protein. As a result of this aberrant CSF1 expression, the bulk of the tumor mass is composed of CSF1R-positive macrophages.^1,5-7Although there are no FDA-approved anticancer therapies categorized as CSF1R inhibitors, the multitargeted tyrosine kinase inhibitor (TKI) imatinib (Gleevec) has been shown to block CSF1R and demonstrate activity in dt-TGCT, prompting the development of more specific CSF1R inhibitors.^8,9 Preclinical study results suggest that this drug class could reprogram TAMs from an M2-like phenotype to a more proinflammatory, antitumor, immunostimulatory phenotype. Treatment with CSF1R inhibitors reduced the number of immunosuppressive TAMs and promoted the production of immunostimulatory cytokines, which resulted in enhanced antitumor immune responses.^8,9

Both monoclonal antibodies (mAbs) and small-molecule TKIs targeting CSF1R and the ligand CSF1 have now been developed and are being evaluated in clinical trials (TABLE), although the available clinical data are limited.

Table. Selected Studies Targeting Colony Stimulating Factor Pathway

Frequent overexpression of CSF1 and a need for novel treatment options made dt-TGCT the ideal target in which to test CSF1R inhibitors. Phase I study findings suggest promising antitumor activity for several of these drugs. Emactuzumab, a CSF1R-binding mAb, was evaluated in 28 patients with dt-TGCT and generated partial responses (PRs) in 79% and complete responses (CRs) in 7%, with stable disease (SD) in 11%.¹⁰ Although emactuzumab is no longer being evaluated in this clinical setting, it is being tested in non-Hodgkin lymphoma, ovarian cancer, and other solid tumors.

More promising is pexidartinib, a CSFR1 TKI. Forty-one patients with dt-TGCT were enrolled in a phase I dose-escalation trial and an additional 23 were enrolled in an extension study. In the extension study, pexidartinib demonstrated an overall response rate (ORR) of 52%, all PRs, and there was a 30% SD rate. Responses usually occurred within the first 4 months of treatment, and the median duration of response lasted in excess of 8 months.¹¹

This prompted the FDA to award breakthrough therapy status to pexidartinib in this indication. The phase III ENLIVEN trial was subsequently initiated as a 2-part double-blind study in which the efficacy of pexidartinib was compared with placebo.

Monotherapy Efficacy Limited

Although Daiichi Sankyo and Plexxikon reported in 2016 that they had suspended enrollment in the trial as a result of 2 reported cases of nonfatal, serious liver toxicity, evaluation of the 121 patients already enrolled continued to completion. Late last year, the companies reported that the trial had met its primary endpoint of tumor response as measured by tumor size reduction. Publication of full details is eagerly anticipated.^12,13Although CSF1R inhibitors have been evaluated as monotherapy, limited effects on clinical efficacy have been reported thus far. In a phase II study in 38 patients with glioblastoma treated with pexidartinib, 18% of patients experienced SD as best response. There were no PRs or CRs, and there was no significant improvement in 6-month progression-free survival.¹⁴

Pexidartinib was also evaluated in a phase I/II trial in 20 heavily pretreated patients with classical Hodgkin lymphoma and demonstrated an ORR of 5%. JNJ-4036527, the development of which has now been halted, showed similar efficacy in this tumor type. Like pexidartinib, ARRY-382 is a CSF1R TKI. In separate phase I studies in patients with advanced solid tumors, both ARRY-382 and emactuzumab demonstrated SD rates of 15% and no objective responses.⁴

Recently, the CSF1R-targeting mAb AMG 820 was tested in a phase I trial in patients with advanced solid tumors. Participants (N = 25) received AMG 820 intravenously at doses of 0.5 mg/kg once weekly or 1.5 to 20 mg/kg every 2 weeks. Among 15 patients who were evaluable for response, 32% had SD as the best response, including 1 patient each with non—small cell lung cancer, paraganglioma, and a pancreatic neuroendocrine tumor.

Combinations Show Promise

The maximum tolerated dose was not reached, and only 1 dose-limiting toxicity (nonreversible grade 3 deafness) was observed. The most frequent treatment-related adverse events (AEs) were periorbital edema, increased aspartate aminotransferase (AST), fatigue, nausea, increased alkaline phosphatase (ALP), and blurred vision.¹⁵Given the limited efficacy of CSF1R inhibitors as monotherapy, the focus has now shifted toward understanding why this is the case and investigating the use of these drugs as part of rational combinations in an effort to boost their efficacy.

In particular, the combination of CSF1R inhibitors and drugs targeting the PD-1 immune checkpoint and its ligands, PD-L1 and PD-L2, have garnered significant attention. Preclinical studies’ results suggest that tumors treated with CSF1R inhibitors may upregulate the PD-L1 protein in order to compensate for the loss of immunosuppressive signaling.

The results of an ongoing phase I/II trial evaluating the combination of ARRY-382 and pembrolizumab (Keytruda) in patients with solid tumors were presented at the 2017 Annual Meeting of the Society for Immunotherapy of Cancer (SITC). The phase I portion of the study has been completed and established a recommended phase II dose of 300 mg daily for ARRY-382 in combination with 2 mg/ kg pembrolizumab administered intravenously every 3 weeks.

Among 19 patients, confirmed PRs occurred in 2 patients, 1 with pancreatic ductal adenocarcinoma and the other with ovarian cancer. The participants also included patients with colorectal cancer, gastric cancer, melanoma, and triple-negative breast cancer. The most common AEs of any grade were increased serum enzyme levels, fatigue, pyrexia, and nausea. Grade 3/4 AEs most frequently included increased levels of AST, creatine kinase, lipase, ALP, and alanine aminotransferase, as well as rash and anemia. The phase II portion of the study is currently enrolling patients.¹⁶

Findings from another combination study also were presented at the SITC meeting. In a phase I dose-escalation and expansion study in several types of solid tumors, cabiralizumab, a CSF1Rtargeting mAb, was evaluated as monotherapy and in combination with nivolumab (Opdivo), which targets PD-1. The dose-escalation portion of the trial, in which patients were administered doses of cabiralizumab ranging from 1 to 6 mg/kg in combination with nivolumab 3 mg/kg every 2 weeks, established a recommended phase II dose for cabiralizumab of 4 mg/kg.

This dose is subsequently being evaluated in the ongoing dose-expansion portion of the study in 195 patients. The data presented at SITC reported a confirmed ORR of 13% among 33 heavily pretreated patients with pancreatic cancer. Interestingly, all responses occurred in patients who had microsatellite-stable disease, a group that typically does not derive benefit from PD-1/PD-L1 inhibitors. This suggests that this combination not only may improve the efficacy of CSF1R inhibitors but also could broaden the impact of immune checkpoint inhibitors.

The most common AEs of all grades were serum enzyme elevations, fatigue, periorbital edema, rash, and vomiting. Grade 3/4 AEs also included serum enzyme elevations, hyponatremia, and maculopapular rash. A phase II study of cabiralizumab in combination with nivolumab with or without chemotherapy in pancreatic cancer is currently enrolling participants.¹⁷

Patient enrollment in a phase I/II study of pexidartinib in combination with pembrolizumab has also recently begun, with the aim of evaluating the combination in 500 patients across 12 cancer types.

Emerging preclinical data suggest that CSF1R inhibition also may prove promising in combination with other types of drugs. For example, study data have shown that TAMs and myeloid cells are attracted to the hypoxic microenvironment that is generated following treatment with antiangiogenic drugs. Since these cells secrete proangiogenic molecules, they can contribute to resistance to antiangiogenic therapies such as bevacizumab (Avastin), which targets vascular endothelial growth factor A. Thus, a combination of CSF1R and antiangiogenic therapy could help to overcome this mechanism of resistance.

References

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