Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours

• 成果类型: Article
• 署名作者: Melero, Ignacio; de Miguel Luken, Maria; de Velasco, Guillermo; Garralda, Elena; Martin-Liberal, Juan; Joerger, Markus; Alonso, Guzman; Goebeler, Maria-Elisabeth; Schuler, Martin; Koenig, David; Dummer, Reinhard; Reig, Maria; Rodriguez Ruiz, Maria-Esperanza; Calvo, Emiliano; Esteban-Villarrubia, Jorge; Oberoi, Arjun; Sabat, Paula; Soto-Castillo, Juan Jose; Koster, Kira-Lee; Saavedra, Omar; Sayehli, Cyrus; Gromke, Tanja; Laeubli, Heinz; Ramelyte, Egle; Fortuny, Marta; Landa-Magdalena, Ana; Moreno, Irene; Torres-Jimenez, Javier; Hernando-Calvo, Alberto; Hess, Dagmar; Racca, Fabricio; Richly, Heike; Schmitt, Andreas M.; Eggenschwiler, Corinne; Sanduzzi-Zamparelli, Marco; Vilalta-Lacarra, Anna; Trojan, Joerg; Koch, Christine; Galle, Peter R.; Foerster, Friedrich; Trajanoski, Zlatko; Hackl, Hubert; Gogolla, Falk; Koll, Florestan J.; Wild, Peter; Chun, Felix Kyoung Hwan; Reis, Henning; Lloyd, Peter; Machacek, Matthias; Gajewski, Thomas F.; Fridman, Wolf H.; Eggermont, Alexander M. M.; Bargou, Ralf; Schoeniger, Sandra; Rueschoff, Josef; Tereshchenko, Anastasiia; Zink, Carina; da Silva, Antonio; Lichtenegger, Felix S.; Akdemir, Julia; Ruediger, Manfred; L'Huillier, Phil; Dutta, Aradhana; Haake, Markus; Auckenthaler, Alexandra; Gjorgjioska, Ana; Roessler, Bernhard; Hermann, Frank; Liebig, Mara; Reichhardt, Daniela; Schuberth-Wagner, Christine; Wischhusen, Joerg; Fettes, Petra; Auer, Marlene; Klar, Kathrin; Leo, Eugen
• 署名单位: University of Navarra; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; University of Oxford; Hospital Universitario 12 de Octubre; Hospital Universitari Vall d'Hebron; Vall d'Hebron Institut d'Oncologia (VHIO); Institut Catala d'Oncologia; Kantonsspital St. Gallen; quironsalud Group; University of Wurzburg; University of Duisburg Essen; University of Basel; University of Zurich; University Zurich Hospital; University of Barcelona; Hospital Clinic de Barcelona; IDIBAPS; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; University of Navarra; Goethe University Frankfurt; Goethe University Frankfurt Hospital; Johannes Gutenberg University of Mainz; Medical University of Innsbruck; Goethe University Frankfurt; Goethe University Frankfurt Hospital; Goethe University Frankfurt; Goethe University Frankfurt Hospital; University of Chicago; University of Chicago Medical Center; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Universite Paris Cite; Utrecht University; Utrecht University Medical Center; Princess Maxima Center; University of Munich; University of Wurzburg
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3257
• DOI: 10.1038/s41586-024-08305-z
• 发表日期: 2025-01-30
• 关键词: cancer; pembrolizumab; gdf15; mic-1

摘要

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-gamma-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.