These findings identify CLEVER-1+ TAMs as both biomarker and functional mediator of anti-PD-1 therapy resistance, providing a rationale for combining bexmarilimab with immune checkpoint blockade in GC. In this commentary, we discuss the mechanistic significance, translational potential, and clinical prospects of CLEVER-1 blockade to overcome immunotherapy resistance in GC.

The humanized anti-Clever-1 IgG4 antibody, bexmarilimab, is under clinical investigation for treating solid tumors (NCT03733990) and hematological malignancies (NCT05428969)... These findings identify sClever-1 as a previously unrecognized, immunosuppressive mediator in cancer that operates independently of cellular Clever-1 expression. sClever-1 may serve as both a therapeutic target and biomarker to guide immunotherapy strategies.

P1/2, N=181, Active, not recruiting, Faron Pharmaceuticals Ltd | Recruiting --> Active, not recruiting | Trial completion date: Dec 2025 --> Apr 2026 | Trial primary completion date: Apr 2025 --> Apr 2026

P1/2, N=181, Recruiting, Faron Pharmaceuticals Ltd | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Apr 2025

Hepatic melanoma metastases show resistance to Stabilin-1 targeting approaches. This suggests that anti-Stab1 therapies should be considered with respect to the tumor entity or target organs.

P1/2, N=181, Recruiting, Faron Pharmaceuticals Ltd | Trial primary completion date: Dec 2023 --> Dec 2024

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.

P1/2, N=216, Completed, Faron Pharmaceuticals Ltd | Active, not recruiting --> Completed | Trial completion date: Nov 2024 --> Oct 2023

We further showed that bexmarilimab was most efficacious in macrophages with low baseline IFN signaling, as chronic IFNγ priming abolished bexmarilimab-induced TNFα release. These results highlight an approach to target immunologically cold tumors and to increase the likelihood of their subsequent response to immune checkpoint inhibitors.

Treatment of AML bone marrow cells with BEX alone or in combination with azacitidine/venetoclax results in enhanced antigen presentation capacity and increased activation markers on effector T cells with synergistic effect on cell death. Additional clinical and pharmacodynamic data of the completed Ph1 of the study will be presented during the meeting. Ph2 of BEX plus azacitidine will open in the 2nd half of 2023 in HMA-failed r/r AML and/or higher risk MDS patients.

P1/2, N=216, Active, not recruiting, Faron Pharmaceuticals Ltd | Trial primary completion date: Nov 2024 --> Sep 2023

Conclusions Bexmarilimab demonstrates promising anti-tumour activity as a monotherapy in several refractory solid tumours. A dose of 1mg/kg Q3W is considered feasible for further monotherapy studies in solid tumors.