University of Oulu

Reetta Virtakoivu, Jenna H. Rannikko, Miro Viitala, Felix Vaura, Akira Takeda, Tapio Lönnberg, Jussi Koivunen, Panu Jaakkola, Annika Pasanen, Shishir Shetty, Maja J.A. de Jonge, Debbie Robbrecht, Yuk Ting Ma, Tanja Skyttä, Anna Minchom, Sirpa Jalkanen, Matti K. Karvonen, Jami Mandelin, Petri Bono, Maija Hollmén; 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. Clin Cancer Res 1 August 2021; 27 (15): 4205–4220. https://doi.org/10.1158/1078-0432.CCR-20-4862

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

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Author: Virtakoivu, Reetta1; Rannikko, Jenna H.1,2; Viitala, Miro1,2;
Organizations: 1MediCity Research Laboratory, University of Turku, Turku, Finland
2Turku Doctoral Program of Molecular Medicine, University of Turku, Turku, Finland
3Turku Bioscience, University of Turku, Turku, Finland
4Oulu University Hospital, MRC Oulu, Oulu, Finland
5Department of Oncology and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Finland
6Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
7Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
8Erasmus MC/Cancer Institute, Rotterdam, the Netherlands
9Tampere University Hospital, Tampere, Finland
10Drug Development Unit, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Sutton, United Kingdom
11Faron Pharmaceuticals, Turku, Finland
12Terveystalo Finland, Helsinki, Finland
13University of Helsinki, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022022420733
Language: English
Published: American Association for Cancer Research, 2021
Publish Date: 2022-02-24
Description:

Abstract

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.

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Series: Clinical cancer research
ISSN: 1078-0432
ISSN-E: 1557-3265
ISSN-L: 1078-0432
Volume: 27
Issue: 15
Pages: 4205 - 4220
DOI: 10.1158/1078-0432.CCR-20-4862
OADOI: https://oadoi.org/10.1158/1078-0432.CCR-20-4862
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Funding: This study was funded by the Academy of Finland (A. Takeda, T. Lönnberg, S. Jalkanen, and M. Hollmén), Emil Aaltonen Foundation (R. Virtakoivu), Maud Kuistila Memorial Foundation, Oskar Öflund Foundation, Ida Montin Foundation (all to M. Viitala), Cancer Research UK fellowship C53575/A29959 (S. Shetty), Sigrid Jusélius Foundation (M. Hollmén), and the Finnish Cancer Foundations (M. Viitala and M. Hollmén). This project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement no. 960914. Faron Pharmaceuticals sponsored the MATINS trial. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Copyright information: © 2021 The Authors; Published by the American Association for Cancer Research This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs International 4.0 License.
  https://creativecommons.org/licenses/by-nc-nd/4.0/