Based on part I/II of the first-in-human MATINS trial, Rannikko et al. report that bexmarilimab, an antibody targeting Clever-1 on monocytes/macrophages, was well tolerated, with low-grade treatment-related AEs, immune activation, and disease stabilization as a monotherapy in several late-stage, treatment-refractory, metastatic solid tumors. Durable disease stabilization was associated with improved survival, high pre-treatment intratumoral Clever-1 positivity, and systemic increases in circulating IFNγ levels. Spatial transcriptomics profiling showed macrophage reprogramming and stimulation of IFNγ and TCR signaling in responding patients.
Contributed by Shishir Pant
ABSTRACT: Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.
Author Info: (1) MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland; Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland. (2)
Author Info: (1) MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland; Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland. (2) Institut Gustave Roussy, Paris and Centre Leon Berard in Lyon, Lyon, France. (3) START-CIOCC HM Sanchinarro, Madrid, Spain. (4) Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. (5) Erasmus Medical Center/Cancer Institute, Rotterdam, the Netherlands. (6) Tampere University Hospital, Tampere, Finland. (7) Oulu University Hospital, University of Oulu, Oulu, Finland. (8) University of Birmingham/University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. (9) University of Birmingham/University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. (10) The Christie NHS Foundation Trust, Manchester, UK. (11) Mays Cancer Center, UT Health San Antonio, San Antonio, TX, USA. (12) Department of Oncology, Turku University Hospital and University of Turku, Turku, Finland. (13) Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK. (14) INDIVIDRUG Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland. (15) Faron Pharmaceuticals Ltd, Turku, Finland. (16) Faron Pharmaceuticals Ltd, Turku, Finland. (17) Faron Pharmaceuticals Ltd, Turku, Finland. (18) INDIVIDRUG Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Wihuri Research Institute, Helsinki, Finland. (19) Oulu University Hospital, University of Oulu, Oulu, Finland; Faron Pharmaceuticals Ltd, Turku, Finland. (20) Drug Development Unit, Royal Marsden Hospital/Institute of Cancer Research, Sutton, UK. (21) MediCity Research Laboratory and InFLAMES Flagship, University of Turku, Turku, Finland; Faron Pharmaceuticals Ltd, Turku, Finland. Electronic address: maijal@utu.fi. (22) Terveystalo Finland and University of Helsinki, Helsinki, Finland. Electronic address: petri.bono@terveystalo.com.
