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

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Title: Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours
Authors: Ignacio Melero, Maria de Miguel Luken, Guillermo de Velasco, Elena Garralda, Juan Martín-Liberal, Markus Joerger, Guzman Alonso, Maria-Elisabeth Goebeler, Martin Schuler, David König, Reinhard Dummer, Maria Reig, Maria-Esperanza Rodriguez Ruiz, Emiliano Calvo, Jorge Esteban-Villarrubia, Arjun Oberoi, Paula Sabat, Juan José Soto-Castillo, Kira-Lee Koster, Omar Saavedra, Cyrus Sayehli, Tanja Gromke, Heinz Läubli, Egle Ramelyte, Marta Fortuny, Ana Landa-Magdalena, Irene Moreno, Javier Torres-Jiménez, Alberto Hernando-Calvo, Dagmar Hess, Fabricio Racca, Heike Richly, Andreas M. Schmitt, Corinne Eggenschwiler, Marco Sanduzzi-Zamparelli, Anna Vilalta-Lacarra, Jörg Trojan, Christine Koch, Peter R. Galle, Friedrich Foerster, Zlatko Trajanoski, Hubert Hackl, Falk Gogolla, Florestan J. Koll, Peter Wild, Felix Kyoung Hwan Chun, Henning Reis, Peter Lloyd, Matthias Machacek, Thomas F. Gajewski, Wolf H. Fridman, Alexander M. M. Eggermont, Ralf Bargou, Sandra Schöniger, Josef Rüschoff, Anastasiia Tereshchenko, Carina Zink, Antonio da Silva, Felix S. Lichtenegger, Julia Akdemir, Manfred Rüdiger, Phil L’Huillier, Aradhana Dutta, Markus Haake, Alexandra Auckenthaler, Ana Gjorgjioska, Bernhard Rössler, Frank Hermann, Mara Liebig, Daniela Reichhardt, Christine Schuberth-Wagner, Jörg Wischhusen, Petra Fettes, Marlene Auer, Kathrin Klar, Eugen Leo
Contributors: Institut Català de la Salut, [Melero I] Clínica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. Nuffield Department of Medicine, University of Oxford, Oxford, UK. [de Miguel Luken M] START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain. [de Velasco G] Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. [Garralda E, Oberoi A, Hernando-Calvo A] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Martín-Liberal J] Medical Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Spain. [Joerger M] Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland, Vall d'Hebron Barcelona Hospital Campus, MS Hematologie
Source: Nature
Scientia
Scientia. Dipòsit d'Informació Digital del Departament de Salut
instname
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Male, Growth Differentiation Factor 15, Lung Neoplasms, Other subheadings::Other subheadings::/therapeutic use, Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia, FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos, Programmed Cell Death 1 Receptor, Medizin, Otros calificadores::Otros calificadores::/uso terapéutico, Medicaments antineoplàstics - Ús terapèutic, Article, B7-H1 Antigen, DISEASES::Neoplasms, COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos::inmunoterapia antineoplásica, Neoplasms, CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents::Antineoplastic Agents, Immunological, Tumor Microenvironment, PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm, Humans, General, Immune Checkpoint Inhibitors, Other subheadings::Other subheadings::Other subheadings::/drug therapy, Anticossos monoclonals - Ús terapèutic, CHEMICALS AND DRUGS::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Antibodies, Neutralizing, Middle Aged, Antibodies, Neutralizing, Nivolumab, ENFERMEDADES::neoplasias, Drug Resistance, Neoplasm, Càncer - Immunoteràpia, Female, COMPUESTOS QUÍMICOS Y DROGAS::aminoácidos, péptidos y proteínas::proteínas::proteínas sanguíneas::inmunoproteínas::inmunoglobulinas::anticuerpos::anticuerpos neutralizantes
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-024-08305-z
Access URL: https://pubmed.ncbi.nlm.nih.gov/39663448
https://hdl.handle.net/11351/12692
https://hdl.handle.net/11588/993426
https://dspace.library.uu.nl/handle/1874/459760
https://www.ncbi.nlm.nih.gov/pubmed/39663448
https://doi.org/10.1038/s41586-024-08305-z
https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&origin=inward&scp=85211775849
Rights: CC BY NC ND
Accession Number: edsair.doi.dedup.....5353a0bdf8f44a60083a0df9a0315b04
Database: OpenAIRE
Description
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.
ISSN:14764687
00280836
DOI:10.1038/s41586-024-08305-z