A multi-institutional clinical trial led by the University of Navarra, Spain, has revealed that inhibiting growth differentiation factor 15 (GDF-15) can effectively counteract resistance to anti-PD-1 and anti-PD-L1 therapies in solid tumors. The GDFATHER-1/2a trial, published in Nature, explored enhanced immunotherapeutic strategies using visugromab, a neutralizing anti-GDF-15 antibody, in combination with the anti-PD-1 antibody nivolumab.
Overcoming Immunotherapy Resistance
Cancer immunotherapies targeting immune checkpoint molecules have revolutionized treatment across various cancer types, significantly improving patient outcomes. However, treatments are often limited by poor response rates and unmitigated tumor progression. Factors within the tumor microenvironment, including cytokines like GDF-15, are thought to contribute to immune suppression and resistance to treatment.
The Phase 1/2a clinical trial enrolled patients with advanced, refractory cancers unresponsive to prior anti-PD-1 or anti-PD-L1 therapies. The treatment involved escalating doses of visugromab alongside standard nivolumab administration. The study monitored safety, tolerability, and antitumor activity through sequential tumor biopsies and immune cell analysis.
Clinical Results
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 tumor 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 tumor responses.
Enhanced T cell infiltration and activation within tumors 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 signaling and cytotoxic markers, supporting the mechanism by which GDF-15 blockade enhances immune response.
Implications and Future Directions
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 tumors. 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.
