Anti-PD1 and anti-PDL1 mAbs such as nivolumab, pembrolizumab, or atezolizumab have proven superior efficacy over standard-of-care therapy in a variety of indications such as melanoma, non-small-cell lung cancer (NSCLC), bladder cancer, as well as others [37C42]. tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for malignancy patients may vary greatly depending on organ-specific characteristics Levomefolate Calcium of these cells. We evaluate the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting brokers and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future. clinical benefit rate, classical Hodgkin lymphoma, colony-stimulating factor 1, colony-stimulating factor 1 receptor, glioblastoma, National Cancer Institute, National Health Support, objective response rate, partial metabolic response Table 3 Clinical trials with CSF1/CSF1R inhibitors in combination with cancer immunotherapy brokers colorectal malignancy, colony-stimulating factor 1, colony-stimulating factor 1 receptor, cytotoxic T-lymphocyte-associated protein 4, glioblastoma, gastrointestinal stromal tumor, monoclonal antibody, microsatellite stable, non-small cell lung malignancy, programmed cell death protein Levomefolate Calcium 1, programmed cell death ligand 1, renal cell carcinoma, squamous cell carcinoma of the head and neck, triple-negative breast malignancy, urothelial bladder carcinoma Among the class of small molecules, pexidartinib (PLX3397), an oral tyrosine kinase inhibitor of CSF1R, cKIT, mutant fms-like tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptor (PDGFR)-, is the subject of the broadest clinical development program in monotherapy, with completed or ongoing studies in c-kit-mutated melanoma, prostate malignancy, glioblastoma (GBM), classical Hodgkin lymphoma (cHL), neurofibroma, sarcoma, and leukemias. Additional CSF1R-targeting small molecules, including ARRY-382, PLX7486, BLZ945, and JNJ-40346527, are currently being investigated in solid tumors and cHL. mAbs in clinical development include emactuzumab, AMG820, IMC-CS4, cabiralizumab, MCS110, and PD-0360324, with the latter two being the only compounds targeting the ligand CSF1. A phase 2 study in 38 patients with recurrent GBM treated with pexidartinib did not show significant improvement in 6-month progression-free survival (PFS) compared to historical control data. Of 38 patients, seven (18%) experienced stable disease; no partial or total responses were observed [14]. An objective response rate (ORR) of 5% was reported with single agent PLX3397 in 20 greatly pre-treated Levomefolate Calcium patients with cHL [15]. Comparable efficacy in relapsed or refractory cHL was exhibited with JNJ-40346527 in a phase 1/2 clinical study. Out of 21 patients enrolled, one showed a complete response (ORR 5%) and 11 (52%) experienced stable disease [16]. Results from a phase 1 study investigating ARRY-382 in advanced solid tumors were recently reported by Bendell et al. Out of 26 patients, four (15%) experienced stable disease, and no objective responses were observed [17]. A phase 1/2 study with BLZ945 in solid tumors is usually ongoing. Data from a phase 1 dose-escalation and growth study investigating emactuzumab showed partial metabolic responses in fluorodeoxyglucose-positron emission tomography in 5/44 (11%) patients and stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) in 6/40 (15%) patients [18]. In addition, the study provided proof of mechanism, demonstrating significant TAM reduction with emactuzumab in paired pre- and on-treatment tumor biopsies (Fig.?2). Open in a separate windows Fig. 2 Depletion of tumor-associated macrophages with emactuzumab in malignancy patients. Immunohistochemistry of paired tumor biopsies from a representative ovarian malignancy individual illustrating co-localization and reduction of CD68+CD163+ TAM (upper panel) and CSF1R+ cells (lower panel) after 4?weeks/two infusions of emactuzumab at the 1000?mg dose level. Permission for re-use granted by I. Klaman [18] Papadopoulos et al. reported that 6/25 patients (24%) treated with AMG820 experienced a best overall response of stable Rabbit polyclonal to TPT1 disease, and one paraganglioma patient (4%) experienced a partial response, with a 40% reduction in tumor burden [19]. Results from two ongoing single-agent phase 1 studies of IMC-CS4 in solid tumors and breast and prostate malignancy are pending. A phase 1/2 study in prostate malignancy of the only anti-CSF1 antibody, MSC110, has been terminated; however, several clinical trials are underway with MSC110 in combination with chemotherapy or immune checkpoint inhibitor therapy (Furniture?2 and ?and33). Table 2 Clinical trials with CSF1/CSF1R inhibitors in combination with anti-tumor therapies (excluding cancer-immunotherapy doublets) clinical benefit rate, colony-stimulating factor 1, colony-stimulating factor 1 receptor, diffuse-type tenosynovial giant cell tumor, glioblastoma, gastrointestinal stromal tumor, malignant peripheral nerve sheath tumor, objective response rate,.
