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
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, 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
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.
©2021 The Authors; Published by the American Association for Cancer Research.
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