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SHR Neuro Cancer Cardio Lipid Metab Microb

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. 2025; 637(8048):1218-1227 Doi: 10.1038/s41586-024-08305-z [OPEN ACCESS]
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Co-authors Med Uni Graz: Koll Florestan Johannes
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Abstract:: Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment¹. Yet, response rates are still limited, and tumour progression commonly occurs². Soluble and cell-bound factors in the tumour microenvironment negatively affect cancer immunity. Recently, growth differentiation factor 15 (GDF-15), a cytokine that is abundantly produced by many cancer types, was shown to interfere with antitumour immune response. In preclinical cancer models, GDF-15 blockade synergistically enhanced the efficacy of anti-PD-1-mediated checkpoint inhibition³. In a first-in-human phase 1-2a study (GDFATHER-1/2a trial, NCT04725474 ), patients with advanced cancers refractory to anti-PD-1 or anti-PD-L1 therapy (termed generally as anti-PD-1/PD-L1 refractoriness) were treated with the neutralizing anti-GDF-15 antibody visugromab (CTL-002) in combination with the anti-PD-1 antibody nivolumab. Here we show that durable and deep responses were achieved in some patients with non-squamous non-small cell lung cancer and urothelial cancer, two cancer entities identified as frequently immunosuppressed by GDF-15 in an in silico screening of approximately 10,000 tumour samples in The Cancer Genome Atlas database. Increased levels of tumour infiltration, proliferation, interferon-γ-related signalling and granzyme B expression by cytotoxic T cells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.
Find related publications in this database (using NLM MeSH Indexing): Growth Differentiation Factor 15 - metabolism; Humans - administration & dosage; Drug Resistance, Neoplasm - drug effects, immunology; Programmed Cell Death 1 Receptor - antagonists & inhibitors, metabolism; B7-H1 Antigen - antagonists & inhibitors, metabolism; Immune Checkpoint Inhibitors - pharmacology, therapeutic use; Neoplasms - immunology, drug therapy, genetics, pathology; Antibodies, Neutralizing - immunology, therapeutic use, pharmacology; Nivolumab - therapeutic use, pharmacology; Female - administration & dosage; Male - administration & dosage; Tumor Microenvironment - immunology, drug effects; Interferon-gamma - metabolism, immunology; Granzymes - metabolism, antagonists & inhibitors