A multi-institutional clinical trial led by the University of Navarra, Spain, found that blocking growth differentiation factor 15 (GDF-15) can counteract resistance to anti-PD-1 and anti-PD-L1 therapies in solid tumours.

Cancer immunotherapies targeting immune checkpoint molecules have revolutionised treatment across various cancer types, significantly improving patient outcomes. Treatments can be limited in some cases by poor response rates and unmitigated tumour progression. Factors within the tumor microenvironment, including cytokines like GDF-15, are thought to contribute to immune suppression and resistance to treatment.

In the study, "Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumors," published in Nature, researchers explored enhanced immunotherapeutic strategies in the GDFATHER-1/2a trial. The team tested the efficacy of visugromab, a neutralising anti-GDF-15 antibody, in combination with the anti-PD-1 antibody nivolumab.

The Phase 1/2a clinical trial enrolled patients with advanced, refractory cancers unresponsive to prior anti-PD-1 or anti-PD-L1 therapies. Treatment involved escalating doses of visugromab alongside standard nivolumab administration. The study monitored safety, tolerability, and antitumor activity through sequential tumour biopsies and immune cell analysis.

Findings demonstrate that the tested combination achieved durable and significant responses in patients with non-squamous non-small cell lung cancer (NSCLC) and urothelial cancer, two tumour types heavily influenced by GDF-15-mediated immunosuppression.

In heavily pretreated patients, 4 out of 27 NSCLC participants and 5 out of 27 urothelial cancer patients exhibited partial or complete tumour responses. Enhanced T-cell infiltration and activation within tumours were observed, indicating a reversal of GDF-15's immunosuppressive effects. Combination therapy was well tolerated, with manageable adverse events.

Pharmacodynamic assessments confirmed increased expression of interferon-γ-related signalling and cytotoxic markers, supporting the mechanism by which GDF-15 blockade enhances immune response.

These findings suggest that targeting GDF-15 may significantly improve the efficacy of existing immune checkpoint inhibitors, offering new hope for patients with resistant solid tumours.

Ongoing and future replication trials are needed to validate these results and to more comprehensively understand the potential of GDF-15 inhibition in broader cancer treatment contexts.