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

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment<sup>1</sup>. Yet, response rates are still limited, and tumour progression commonly occurs<sup>2</sup>. 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 inhibition<sup>3</sup>. 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.

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Nature
Published
2024-12-11
DOI
https://doi.org/10.1038/s41586-024-08305-z
Citations
75
Primary Topic
GDF15 and Related Biomarkers
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article
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35.26
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article

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

Friedrich Foerster, Marco Sanduzzi‐Zamparelli, Eugen Leo, Kira‐Lee Koster et al.
75 citations
Nature
GDF15 and Related Biomarkers
35.26
article

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

Friedrich Foerster, Marco Sanduzzi‐Zamparelli, Eugen Leo, Kira‐Lee Koster, Andreas M. Schmitt, Felix K.‐H. Chun, Egle Ramelyte, Alberto Hernando‐Calvo, Henning Reis, J.J. Soto Castillo, Jorge Esteban-Villarrubia, Fabricio Racca, Ana Gjorgjioska, David König, Petra Fettes, Markus Joerger, Josef Rüschoff, Ignacio Melero, Peter Johannes Wild, Ralf C. Bargou, Guzmán Alonso, Christine Schuberth-Wagner, Dagmar Hess, A. Vilalta, Heinz Läubli, Martin Schüler, Cyrus Sayehli, Heike Richly, Matthias Macháček, Florestan Koll, Hubert Hackl, Alexander M.M. Eggermont, Emiliano Calvo, Markus Haake, Alexandra Auckenthaler, Jörg Wischhusen, Javier Torres-Jiménez, Marlene Auer, Juan Martín-Liberal, Elena Garralda, Ana Landa-Magdalena, A. Oberoi, Peter R. Galle, Falk Gogolla, Irene Moreno, Tanja Gromke, Wolf H. Fridman, Corinne Eggenschwiler, Sandra Schöniger, María Reig, Christine Koch, Marta Fortuny, Anastasiia Tereshchenko, Zlatko Trajanoski, Milton Ruiz, Manfred Rüdiger, Reinhard Dummer, Felix S. Lichtenegger, Omar Saavedra, Kathrin Klar, Paula Sàbat, María de Miguel Luken, Carina Zink, Julia Akdemir, Bernhard Rössler, Guillermo de Velasco, Jörg Trojan, Mara Liebig, Maria-Elisabeth Goebeler, Thomas F. Gajewski, Aradhana Dutta, Frank Hermann, Antonio da Silva, Peter Lloyd, Daniela Reichhardt, Phil L'Huillier
article en
75 citations

Abstract

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment<sup>1</sup>. Yet, response rates are still limited, and tumour progression commonly occurs<sup>2</sup>. 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 inhibition<sup>3</sup>. 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.

NatureVol. 637(8048)
Goethe University Frankfurt (DE), Innsbruck Medical University (AT), Inserm (FR), Universität Innsbruck (AT), Johannes Gutenberg University Mainz (DE), University of St.Gallen (CH), Université Paris Cité (FR), University Hospital of Basel (CH), University Medical Center Utrecht (NL), Sorbonne Université (FR), University of Oxford (GB), Research Institute Hospital 12 de Octubre (ES), University of Chicago Medical Center (US), Centre de Recherche des Cordeliers (FR), University Medical Center of the Johannes Gutenberg University Mainz (DE), University Hospital of Zurich (CH), Comprehensive Cancer Center Mainfranken (DE), Institut Català d'Oncologia (ES), National Center for Tumor Diseases (DE), Hospital Quirónsalud Barcelona (ES), Essen University Hospital (DE), Universitätsklinikum Würzburg (DE), Princess Máxima Center (NL), Vall d'Hebron Hospital Universitari (ES), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (ES), University Hospital Frankfurt (DE), Clinica Universidad de Navarra (ES), Catalent (United States) (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Vall d'Hebron Institute of Oncology (ES), Ludwig-Maximilians-Universität München (DE), Universidad de Navarra (ES)
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