In recent years, a major breakthrough in the treatment of advanced hepatocellular carcinoma has been achieved with the introduction of immunotherapy based on immune checkpoint inhibition. The administration of antibodies against molecules such as PD-1 or its ligand (PD-L1) and CTLA-4 has marked a turning point in this field, improving response rates and increasing patient survival. However, only one-third of patients respond to this treatment, leaving a significant number of patients without effective therapeutic options. This has led to intense scientific efforts to understand the mechanisms of resistance to these therapies and to identify new therapeutic targets that can improve patient outcomes.
One of these research efforts has focused on analyzing GDF-15. This protein, primarily produced by tumor cells, hinders the ability of immune system cells to infiltrate the tumor and attack it.
Recently, Nature published the results of a Phase I/II clinical trial in which patients with solid tumors with metastatic involvement who were resistant to first-line anti-PD-1/L1 therapy—including patients with hepatocellular carcinoma—were treated with a combination of a neutralizing GDF-15 antibody (visugromab) and nivolumab (anti-PD1). The study reports that this combination, in addition to having excellent tolerability, has demonstrated objective and durable tumor burden reductions in some patients who had previously not responded to treatment.
Dr. Ignacio Melero, a member of CIBERONC and the study’s principal investigator, highlights that “GDF-15 is becoming a highly important pharmacological target in cancer treatment. We are looking at results that could potentially transform how we treat cancer, although further studies with larger patient cohorts will be needed to confirm the impact of this new combined therapy.”
This clinical trial has been led by the Clínica Universidad de Navarra and has also involved Spanish centers in Madrid and Barcelona. Among them, researchers from the Liver Oncology Unit (BCLC) at Hospital Clínic-IDIBAPS and CIBEREHD collaborated in the hepatocellular carcinoma patient cohort alongside the Clínica Universidad de Navarra, led by Dr. Bruno Sangro of CIBEREHD.
Clinical Impact and Future Research
Dr. Maria Reig, head of the Liver Oncology Unit at Hospital Clínic and the Liver Oncology (BCLC) group at IDIBAPS and CIBEREHD, and co-author of the study, emphasizes: “We are at a key moment for patients with hepatocellular carcinoma, as it is one of the cancers most resistant to immunotherapy. If these results are confirmed in the ongoing clinical trial, we will be able to extend the lives of these patients.”
Study reference:
Melero I, de Miguel Luken M, de Velasco G, Garralda E, Martín-Liberal J, Joerger M, Alonso G, Goebeler ME, Schuler M, König D, Dummer R, Reig M, Rodriguez Ruiz ME, Calvo E, Esteban-Villarrubia J, Oberoi A, Sabat P, Soto-Castillo JJ, Koster KL, Saavedra O, Sayehli C, Gromke T, Läubli H, Ramelyte E, Fortuny M, Landa-Magdalena A, Moreno I, Torres-Jiménez J, Hernando-Calvo A, Hess D, Racca F, Richly H, Schmitt AM, Eggenschwiler C, Sanduzzi-Zamparelli M, Vilalta-Lacarra A, Trojan J, Koch C, Galle PR, Foerster F, Trajanoski Z, Hackl H, Gogolla F, Koll FJ, Wild P, Chun FKH, Reis H, Lloyd P, Machacek M, Gajewski TF, Fridman WH, Eggermont AMM, Bargou R, Schöniger S, Rüschoff J, Tereshchenko A, Zink C, da Silva A, Lichtenegger FS, Akdemir J, Rüdiger M, L'Huillier P, Dutta A, Haake M, Auckenthaler A, Gjorgjioska A, Rössler B, Hermann F, Liebig M, Reichhardt D, Schuberth-Wagner C, Wischhusen J, Fettes P, Auer M, Klar K, Leo E. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature. 2024 Dec 11. doi: 10.1038/s41586-024-08305-z. Epub ahead of print. PMID: 39663448.
