2. Academic Validation
  3. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours

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

  • Nature. 2025 Jan;637(8048):1218-1227. doi: 10.1038/s41586-024-08305-z.
Ignacio Melero 1 2,  Maria de Miguel Luken 3,  Guillermo de Velasco 4,  Elena Garralda 5,  Juan Martín-Liberal 6,  Markus Joerger 7,  Guzman Alonso 8,  Maria-Elisabeth Goebeler 9,  Martin Schuler 10 11,  David König 12,  Reinhard Dummer 13,  Maria Reig 14 15,  Maria-Esperanza Rodriguez Ruiz 16,  Emiliano Calvo 3,  Jorge Esteban-Villarrubia 4,  Arjun Oberoi 5,  Paula Sabat 6,  Juan José Soto-Castillo 6,  Kira-Lee Koster 7,  Omar Saavedra 8,  Cyrus Sayehli 9,  Tanja Gromke 10 11,  Heinz Läubli 12,  Egle Ramelyte 13,  Marta Fortuny 14 15,  Ana Landa-Magdalena 16,  Irene Moreno 3,  Javier Torres-Jiménez 4,  Alberto Hernando-Calvo 5,  Dagmar Hess 7,  Fabricio Racca 8,  Heike Richly 10 11,  Andreas M Schmitt 12,  Corinne Eggenschwiler 13,  Marco Sanduzzi-Zamparelli 14 15,  Anna Vilalta-Lacarra 16,  Jörg Trojan 17,  Christine Koch 17,  Peter R Galle 18,  Friedrich Foerster 18,  Zlatko Trajanoski 19,  Hubert Hackl 19,  Falk Gogolla 19,  Florestan J Koll 20,  Peter Wild 21,  Felix Kyoung Hwan Chun 20,  Henning Reis 21,  Peter Lloyd 22,  Matthias Machacek 23,  Thomas F Gajewski 24,  Wolf H Fridman 25,  Alexander M M Eggermont 26 27,  Ralf Bargou 28,  Sandra Schöniger 29,  Josef Rüschoff 29,  Anastasiia Tereshchenko 29,  Carina Zink 30,  Antonio da Silva 31,  Felix S Lichtenegger 32,  Julia Akdemir 32,  Manfred Rüdiger 32,  Phil L'Huillier 32,  Aradhana Dutta 32,  Markus Haake 32,  Alexandra Auckenthaler 32,  Ana Gjorgjioska 32,  Bernhard Rössler 32,  Frank Hermann 32,  Mara Liebig 32,  Daniela Reichhardt 32,  Christine Schuberth-Wagner 32,  Jörg Wischhusen 33,  Petra Fettes 32,  Marlene Auer 32,  Kathrin Klar 32,  Eugen Leo 34
Affiliations

Affiliations

  • 1 Clínica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. imelero@unav.es.
  • 2 Nuffield Department of Medicine, University of Oxford, Oxford, UK. imelero@unav.es.
  • 3 START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain.
  • 4 Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain.
  • 5 Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain.
  • 6 Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Spain.
  • 7 Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland.
  • 8 NEXT Oncology Phase I Unit/IOB - Hospital Quirónsalud Barcelona, Barcelona, Spain.
  • 9 Medizinische Klinik 2, Early Clinical Trial Unit, University Hospital Würzburg, Würzburg, Germany.
  • 10 West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany.
  • 11 National Center for Tumor Diseases (NCT) West, Essen, Germany.
  • 12 Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
  • 13 Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
  • 14 Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) & Liver Oncology Unit, Liver Unit, Hospital Clínic, Barcelona, Spain.
  • 15 Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
  • 16 Department of Immunology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
  • 17 Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany.
  • 18 Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
  • 19 Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
  • 20 Department of Urology, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany.
  • 21 Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany.
  • 22 KinDyn Consulting, Warnham, UK.
  • 23 LYO-X AG, Basel, Switzerland.
  • 24 The University of Chicago Medical Center, Chicago, IL, USA.
  • 25 Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France.
  • 26 University Medical Center Utrecht and Princess Máxima Center, Utrecht, The Netherlands.
  • 27 Comprehensive Cancer Center Munich of the Technical University Munich and the Ludwig-Maximilian University, Munich, Germany.
  • 28 Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.
  • 29 Discovery Life Sciences Biomarker Services, Kassel, Germany.
  • 30 Metronomia Clinical Research, Munich, Germany.
  • 31 da Silva Consulting Services, Munich, Germany.
  • 32 CatalYm, Munich, Germany.
  • 33 Department of Gynecology, University Hospital Würzburg, Würzburg, Germany.
  • 34 CatalYm, Munich, Germany. eugen.leo@catalym.com.
PMID: 39663448 DOI: 10.1038/s41586-024-08305-z
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P99100
    98.40%, GDF-15 Neutralizing Antibody