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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Virtakoivu , R , Rannikko , J H , Viitala , M , Vaura , F , Takeda , A , Lonnberg , T , Koivunen , J , Jaakkola , P , Pasanen , A , Shetty , S , de Jonge , M J A , Robbrecht , D , Ma , Y T , Skyttä , T , Minchom , A , Jalkanen , S , Karvonen , M K , Mandelin , J , Bono , P & Hollmen , M 2021 , ' 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 ' , Clinical Cancer Research , vol. 27 , no. 15 , pp. 4205-4220 . https://doi.org/10.1158/1078-0432.CCR-20-4862

Titel: 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
Författare: Virtakoivu, Reetta; Rannikko, Jenna H.; Viitala, Miro; Vaura, Felix; Takeda, Akira; Lonnberg, Tapio; Koivunen, Jussi; Jaakkola, Panu; Pasanen, Annika; Shetty, Shishir; de Jonge, Maja J. A.; Robbrecht, Debbie; Ma, Yuk Ting; Skyttä, Tanja; Minchom, Anna; Jalkanen, Sirpa; Karvonen, Matti K.; Mandelin, Jami; Bono, Petri; Hollmen, Maija
Upphovmannens organisation: HUS Comprehensive Cancer Center
Department of Oncology
Heikki Joensuu / Principal Investigator
University of Helsinki
Datum: 2021-08-01
Språk: eng
Sidantal: 16
Tillhör serie: Clinical Cancer Research
ISSN: 1078-0432
DOI: https://doi.org/10.1158/1078-0432.CCR-20-4862
Permanenta länken (URI): http://hdl.handle.net/10138/334630
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.
Subject: DENDRITIC CELLS
T-CELLS
RECEPTOR
MACROPHAGES
DIFFERENTIATION
HOMEOSTASIS
ENVIRONMENT
STABILIN-1
PATHWAYS
3122 Cancers
Referentgranskad: Ja
Licens: cc_by_nc_nd
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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