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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dc.contributor.author Virtakoivu, Reetta
dc.contributor.author Rannikko, Jenna H.
dc.contributor.author Viitala, Miro
dc.contributor.author Vaura, Felix
dc.contributor.author Takeda, Akira
dc.contributor.author Lonnberg, Tapio
dc.contributor.author Koivunen, Jussi
dc.contributor.author Jaakkola, Panu
dc.contributor.author Pasanen, Annika
dc.contributor.author Shetty, Shishir
dc.contributor.author de Jonge, Maja J. A.
dc.contributor.author Robbrecht, Debbie
dc.contributor.author Ma, Yuk Ting
dc.contributor.author Skyttä, Tanja
dc.contributor.author Minchom, Anna
dc.contributor.author Jalkanen, Sirpa
dc.contributor.author Karvonen, Matti K.
dc.contributor.author Mandelin, Jami
dc.contributor.author Bono, Petri
dc.contributor.author Hollmen, Maija
dc.date.accessioned 2021-09-27T10:16:02Z
dc.date.available 2021-09-27T10:16:02Z
dc.date.issued 2021-08-01
dc.identifier.citation 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
dc.identifier.other PURE: 168788425
dc.identifier.other PURE UUID: 2891657c-d373-48a8-ba42-37ad4f1637f7
dc.identifier.other WOS: 000680860800011
dc.identifier.uri http://hdl.handle.net/10138/334630
dc.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. en
dc.format.extent 16
dc.language.iso eng
dc.relation.ispartof Clinical Cancer Research
dc.rights cc_by_nc_nd
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject DENDRITIC CELLS
dc.subject T-CELLS
dc.subject RECEPTOR
dc.subject MACROPHAGES
dc.subject DIFFERENTIATION
dc.subject HOMEOSTASIS
dc.subject ENVIRONMENT
dc.subject STABILIN-1
dc.subject PATHWAYS
dc.subject 3122 Cancers
dc.title 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 en
dc.type Article
dc.contributor.organization HUS Comprehensive Cancer Center
dc.contributor.organization Department of Oncology
dc.contributor.organization Heikki Joensuu / Principal Investigator
dc.contributor.organization University of Helsinki
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1158/1078-0432.CCR-20-4862
dc.relation.issn 1078-0432
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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