Systemic Blockade of Clever-1 Elicits Lymphocyte Activation Alongside Checkpoint Molecule Downregulation in Patients with Solid Tumors: Results from a Phase I/II Clinical Trial.

Autor:	Virtakoivu R; MediCity Research Laboratory, University of Turku, Turku, Finland., Rannikko JH; MediCity Research Laboratory, University of Turku, Turku, Finland.; Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland., Viitala M; MediCity Research Laboratory, University of Turku, Turku, Finland.; Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland., Vaura F; MediCity Research Laboratory, University of Turku, Turku, Finland., Takeda A; MediCity Research Laboratory, University of Turku, Turku, Finland., Lönnberg T; Turku Bioscience, University of Turku, Turku, Finland., Koivunen J; Oulu University Hospital, MRC Oulu, Oulu, Finland., Jaakkola P; Department of Oncology and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Finland., Pasanen A; Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland., Shetty S; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., de Jonge MJA; Erasmus MC/Cancer Institute, Rotterdam, the Netherlands., Robbrecht D; Erasmus MC/Cancer Institute, Rotterdam, the Netherlands., Ma YT; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom., Skyttä T; Tampere University Hospital, Tampere, Finland., Minchom A; Drug Development Unit, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Sutton, United Kingdom., Jalkanen S; MediCity Research Laboratory, University of Turku, Turku, Finland., Karvonen MK; Faron Pharmaceuticals, Turku, Finland., Mandelin J; Faron Pharmaceuticals, Turku, Finland., Bono P; Terveystalo Finland, Helsinki, Finland.; University of Helsinki, Helsinki, Finland., Hollmén M; MediCity Research Laboratory, University of Turku, Turku, Finland. maijal@utu.fi.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Aug 01; Vol. 27 (15), pp. 4205-4220. Date of Electronic Publication: 2021 Jun 02.
DOI:	10.1158/1078-0432.CCR-20-4862
Abstrakt:	Purpose: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8 + T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. Patients and Methods: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer ( n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. Results: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8 + T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. Conclusions: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer. (©2021 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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