| Autor: |
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 |
| Rok vydání: |
2023 |
| DOI: |
10.1101/2023.04.17.23288693 |
| Popis: |
Clever-1 expression in macrophages contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial was designed to investigate the safety and tolerability of Clever-1 blockade in patients with treatment-refractory solid tumors and to assess preliminary anti- tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab was well tolerated with no observed 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% were observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor positive breast, and biliary tract cancers, which associated with improved survival in a landmark analysis. High pre-treatment intra-tumoral Clever-1 staining and low circulating TNFα correlated with DC. Digital spatial profiling of DC and non-DC tumors with next generation sequencing showed bexmarilimab-induced macrophage activation and robust 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 tumor control in late stage cancer.HighlightsTargeting Clever-1 with bexmarilimab is well toleratedDisease control in late stage cancer can be achieved with bexmarilimab monotherapyLow baseline immune activation associates with bexmarilimab benefitBexmarilimab converts intratumoral macrophages to support adaptive immune responses |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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