Faron Pharmaceuticals has announced groundbreaking research that identifies a previously unknown mechanism of cancer immune evasion, providing new scientific validation for its lead immunotherapy candidate bexmarilimab. The study, published in the peer-reviewed journal Theranostics, reveals how a secreted form of the Clever-1 receptor actively suppresses immune responses and contributes to immunotherapy resistance.
Discovery of Secreted Clever-1 as Immune Suppressor
The research team analyzed plasma samples from 139 breast cancer patients and 193 bexmarilimab-treated clinical trial participants, alongside healthy donors. They discovered that a secreted, truncated form of the Clever-1 receptor (sClever-1) was significantly enriched in the plasma of cancer patients compared to healthy individuals.
"Our research unveils a previously unrecognized mechanism of immune suppression in cancer, where a secreted form of Clever-1 actively hinders T-cell responses," said Maija Hollmén, senior author of the study from MediCity Research Laboratory and InFLAMES Flagship at the University of Turku. "We have shown that sClever-1 operates independently of the cellular receptor and contributes to an immunosuppressive environment."
The study demonstrated that sClever-1, released by macrophages and endothelial cells, binds to activated T cells, impairing their signaling and promoting the differentiation of suppressive T cells. This mechanism contributes directly to tumor immune evasion and represents a novel pathway through which cancers escape immune surveillance.
Link to Immunotherapy Resistance
A critical finding of the research was the association between high sClever-1 levels and resistance to anti-PD-1 checkpoint inhibitors. This discovery positions sClever-1 as a potential biomarker that could guide immunotherapy treatment strategies and help identify patients who may not respond to current checkpoint inhibitor therapies.
In patient-derived tumor explants, the addition of recombinant sClever-1 protein led to a significant increase in the secretion of TGF-β, a key immunosuppressive cytokine. This finding reinforces sClever-1's role in creating and maintaining an immunosuppressive tumor microenvironment.
Bexmarilimab's Mechanism Validated
The study provided direct mechanistic validation for bexmarilimab's therapeutic approach. Treatment with bexmarilimab significantly reduced the release of sClever-1 in cancer patients, and this reduction correlated with decreased engagement on T cells. This finding provides a direct mechanistic link to the peripheral T-cell activation previously observed in bexmarilimab-treated patients.
"These unique findings further solidify our conviction in bexmarilimab's unique mechanism of action," said Petri Bono, Faron's Chief Medical Officer. "The ability of bexmarilimab to reduce systemic levels of the immunosuppressive sClever-1 provides a clear rationale for its potential to overcome immunotherapy resistance."
Broader Therapeutic Implications
The research suggests potential applications beyond cancer treatment. Bono noted that the findings "provide a very intriguing basis of using soluble Clever-1 to inactivate T-cells in conditions where they are attacking our own body, i.e. in a wide range of auto-immune and inflammatory conditions."
Bexmarilimab targets the Clever-1 receptor on macrophages, altering the tumor microenvironment by reprogramming macrophages from an immunosuppressive (M2) state to an immunostimulatory (M1) one. This reprogramming upregulates interferon production and primes the immune system to attack tumors while sensitizing cancer cells to standard of care treatments.
Research Support and Validation
The study was supported by Faron Pharmaceuticals and grants from leading international funding bodies, including Cancer Research UK (CRUK), the NIHR Birmingham Biomedical Research Centre, the Research Council of Finland, and the Sigrid Jusélius Foundation. This broad institutional support underscores the scientific significance of the findings and their potential clinical impact.
The research adds to the growing body of evidence supporting bexmarilimab's development as a potential cornerstone of immunotherapy for patients with aggressive cancers, particularly those who have developed resistance to current checkpoint inhibitor therapies.
