Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial

Jenna h. Rannikko; Loic Verlingue; Maria De miguel; Annika Pasanen; Debbie Robbrecht; Tanja Skytta; Sanna Iivanainen; Shishir Shetty; Yuk ting Ma; Donna m. Graham; Sukeshi patel Arora; Panu Jaakkola; Christina Yap; Yujuan Xiang; Jami Mandelin; Matti k. Karvonen; Juho Jalkanen; Sinem Karaman; Jussi p. Koivunen; Anna Minchom; Maija Hollmén; Petri Bono

doi:10.1016/j.xcrm.2023.101307

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial

Jenna h. Rannikko, Loic Verlingue, Maria De miguel, Annika Pasanen, Debbie Robbrecht, Tanja Skytta, Sanna Iivanainen, Shishir Shetty, Yuk ting Ma, Donna m. Graham, Sukeshi patel Arora, Panu Jaakkola, Christina Yap, Yujuan Xiang, Jami Mandelin, Matti k. Karvonen, Juho Jalkanen, Sinem Karaman, Jussi p. Koivunen, Anna MinchomMaija Hollmén, Petri Bono

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Abstract

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.

Original language	English
Article number	101307
Journal	Cell Reports Medicine
Volume	4
Issue number	12
Early online date	5 Dec 2023
DOIs	https://doi.org/10.1016/j.xcrm.2023.101307
Publication status	Published - 19 Dec 2023

Bibliographical note

Acknowledgments
We thank the study participants, the investigators, and the research team who contributed to the study. We also want to thank Mari Parsama, Teija Kanasuo, Riikka Sjöroos, Sari Mäki, and Maritta Pohjansalo for excellent technical assistance. GeoMx Digital Spatial Profiling was performed at FIMM Single-Cell Analytics and Sequencing units supported by HiLIFE and Biocenter Finland. This study was funded by Faron Pharmaceuticals (Turku, Finland), European Union’s Horizon 2020 research and innovation program (ID: 960914), the Academy of Finland (M.H.), Business Finland (M.H.), Cancer Society of Finland (M.H. and J.H.R.), the Sigrid Jusélius Foundation (M.H.), Orion Research Foundation (J.H.R.), and the Paulo Foundation (J.H.R.). The graphical abstract was created with BioRender.

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Rannikko, J. H., Verlingue, L., De miguel, M., Pasanen, A., Robbrecht, D., Skytta, T., Iivanainen, S., Shetty, S., Ma, Y. T., Graham, D. M., Arora, S. P., Jaakkola, P., Yap, C., Xiang, Y., Mandelin, J., Karvonen, M. K., Jalkanen, J., Karaman, S., Koivunen, J. P., ... Bono, P. (2023). Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial. Cell Reports Medicine, 4(12), Article 101307. https://doi.org/10.1016/j.xcrm.2023.101307

@article{7eb7242af3194640a62cc65f2df3db2f,

title = "Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial",

abstract = "Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.",

author = "Rannikko, {Jenna h.} and Loic Verlingue and {De miguel}, Maria and Annika Pasanen and Debbie Robbrecht and Tanja Skytta and Sanna Iivanainen and Shishir Shetty and Ma, {Yuk ting} and Graham, {Donna m.} and Arora, {Sukeshi patel} and Panu Jaakkola and Christina Yap and Yujuan Xiang and Jami Mandelin and Karvonen, {Matti k.} and Juho Jalkanen and Sinem Karaman and Koivunen, {Jussi p.} and Anna Minchom and Maija Hollm{\'e}n and Petri Bono",

note = "Acknowledgments We thank the study participants, the investigators, and the research team who contributed to the study. We also want to thank Mari Parsama, Teija Kanasuo, Riikka Sj{\"o}roos, Sari M{\"a}ki, and Maritta Pohjansalo for excellent technical assistance. GeoMx Digital Spatial Profiling was performed at FIMM Single-Cell Analytics and Sequencing units supported by HiLIFE and Biocenter Finland. This study was funded by Faron Pharmaceuticals (Turku, Finland), European Union{\textquoteright}s Horizon 2020 research and innovation program (ID: 960914), the Academy of Finland (M.H.), Business Finland (M.H.), Cancer Society of Finland (M.H. and J.H.R.), the Sigrid Jus{\'e}lius Foundation (M.H.), Orion Research Foundation (J.H.R.), and the Paulo Foundation (J.H.R.). The graphical abstract was created with BioRender.",

year = "2023",

month = dec,

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doi = "10.1016/j.xcrm.2023.101307",

language = "English",

volume = "4",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

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Rannikko, JH, Verlingue, L, De miguel, M, Pasanen, A, Robbrecht, D, Skytta, T, Iivanainen, S, Shetty, S , Ma, YT, Graham, DM, Arora, SP, Jaakkola, P, Yap, C, Xiang, Y, Mandelin, J, Karvonen, MK, Jalkanen, J, Karaman, S, Koivunen, JP, Minchom, A, Hollmén, M & Bono, P 2023, 'Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial', Cell Reports Medicine, vol. 4, no. 12, 101307. https://doi.org/10.1016/j.xcrm.2023.101307

TY - JOUR

T1 - Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors

T2 - The phase I/II first-in-human MATINS trial

AU - Rannikko, Jenna h.

AU - Verlingue, Loic

AU - De miguel, Maria

AU - Pasanen, Annika

AU - Robbrecht, Debbie

AU - Skytta, Tanja

AU - Iivanainen, Sanna

AU - Shetty, Shishir

AU - Ma, Yuk ting

AU - Graham, Donna m.

AU - Arora, Sukeshi patel

AU - Jaakkola, Panu

AU - Yap, Christina

AU - Xiang, Yujuan

AU - Mandelin, Jami

AU - Karvonen, Matti k.

AU - Jalkanen, Juho

AU - Karaman, Sinem

AU - Koivunen, Jussi p.

AU - Minchom, Anna

AU - Hollmén, Maija

AU - Bono, Petri

N1 - Acknowledgments We thank the study participants, the investigators, and the research team who contributed to the study. We also want to thank Mari Parsama, Teija Kanasuo, Riikka Sjöroos, Sari Mäki, and Maritta Pohjansalo for excellent technical assistance. GeoMx Digital Spatial Profiling was performed at FIMM Single-Cell Analytics and Sequencing units supported by HiLIFE and Biocenter Finland. This study was funded by Faron Pharmaceuticals (Turku, Finland), European Union’s Horizon 2020 research and innovation program (ID: 960914), the Academy of Finland (M.H.), Business Finland (M.H.), Cancer Society of Finland (M.H. and J.H.R.), the Sigrid Jusélius Foundation (M.H.), Orion Research Foundation (J.H.R.), and the Paulo Foundation (J.H.R.). The graphical abstract was created with BioRender.

PY - 2023/12/19

Y1 - 2023/12/19

N2 - Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.

AB - Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.

U2 - 10.1016/j.xcrm.2023.101307

DO - 10.1016/j.xcrm.2023.101307

M3 - Article

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 12

M1 - 101307

ER -

Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors: The phase I/II first-in-human MATINS trial

Abstract

Bibliographical note

UN SDGs

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