A COMBINATION of the anti-GDF-15 antibody visugromab and anti-PD-1 therapy nivolumab has shown promising results in overcoming resistance to immune checkpoint inhibition in patients with advanced cancers.
Immune checkpoint inhibitors targeting PD-1 and PD-L1 have revolutionised cancer treatment, becoming the standard of care for many solid tumours. However, response rates remain limited, with many patients experiencing tumour progression despite therapy. Tumour microenvironment factors, including cytokines such as growth differentiation factor 15 (GDF-15), have been implicated in immune evasion. GDF-15 is abundantly produced by many cancer types and has been shown to suppress the anti-tumour immune response. In preclinical models, blocking GDF-15 enhanced the efficacy of PD-1 inhibition, leading to the hypothesis that neutralising this cytokine could improve immunotherapy outcomes in resistant cancers.
A Phase 1–2a clinical trial (GDFATHER-1/2a, NCT04725474) evaluated visugromab, a neutralising anti-GDF-15 antibody, in combination with nivolumab in patients with advanced cancers refractory to prior PD-1/PD-L1 therapy. Among the participants, those with non-squamous non-small cell lung cancer and urothelial carcinoma exhibited particularly notable responses. Immunohistochemical analyses revealed increased tumour infiltration by cytotoxic T cells, higher levels of interferon-γ-related signalling, and enhanced granzyme B expression, indicating improved immune activation. These findings suggest that blocking GDF-15 restores anti-tumour immunity in patients previously unresponsive to checkpoint inhibitors.
This study highlights the potential of GDF-15 inhibition as a novel strategy to overcome resistance to PD-1 blockade. Clinically, these results suggest that visugromab could expand treatment options for patients with advanced cancers who have exhausted existing immunotherapies.
Jenna Lorge, EMJ
Reference
Melero I et al. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature. 2025;637:1218-27.
