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December 15, 2024
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Hybrid Gold

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

Publicated to:Nature. - 2024-12-11 (), DOI: 10.1038/s41586-024-08305-z

Authors: Ignacio Melero; María de Miguel Luken; Guillermo de Velasco; Elena Garralda; Juan Martin‐Liberal; Markus Joerger; Guzmán Alonso; Maria-Elisabeth Goebeler; Martin Schüler; David König; Reinhard Dummer; María Reig; Milton Ruiz; Emiliano Calvo; Jorge Esteban-Villarrubia; A. Oberoi; Paula Sàbat; J.J. Soto Castillo; Kira‐Lee Koster; Omar Saavedra; Cyrus Sayehli; Tanja Gromke; Heinz Läubli; Egle Ramelyte; Marta Fortuny; Ana Landa-Magdalena; Irene Moreno; J. Torres Jiménez; Alberto Hernando‐Calvo; Dagmar Hess; Fabricio Racca; Heike Richly; Andreas M. Schmitt; Corinne Eggenschwiler; Marco Sanduzzi‐Zamparelli; A. Vilalta; Jörg Trojan; Christine Koch; Peter R. Galle; Friedrich Foerster; Zlatko Trajanoski; Hubert Hackl; Falk Gogolla; Florestan Koll; Peter J. Wild; Felix K.‐H. Chun; Henning Reis; Peter Lloyd; Matthias Macháček; Thomas F. Gajewski; Wolf H. Fridman; Alexander M.M. Eggermont; Ralf C. 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

Affiliations

CatalYm, Munich, Germany. - Author
CatalYm, Munich, Germany. eugen.leo@catalym.com. - Author
Centre de Recherche des Cordeliers, INSERM U1138, Sorbonne Université, Université Paris Cité, Paris, France. - Author
Clínica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. imelero@unav.es. - Author
da Silva Consulting Services, Munich, Germany. - Author
Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. - Author
Department of Gastroenterology, Hepatology and Endocrinology, University Hospital Frankfurt, Frankfurt, Germany. - Author
Department of Gynecology, University Hospital Würzburg, Würzburg, Germany. - Author
Department of Immunology and Oncology, Clínica Universidad de Navarra, Pamplona, Spain. - Author
Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. - Author
Department of Medical Oncology & Hematology, Cantonal Hospital, St Gallen, Switzerland. - Author
Department of Medical Oncology, University Hospital Basel, Basel, Switzerland. - Author
Department of Urology, Hospital of the Goethe University Frankfurt, Frankfurt am Main, Germany. - Author
Discovery Life Sciences Biomarker Services, Kassel, Germany. - Author
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) & Liver Oncology Unit, Liver Unit, Hospital Clínic, Barcelona, Spain. - Author
Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. - Author
KinDyn Consulting, Warnham, UK. - Author
LYO-X AG, Basel, Switzerland. - Author
Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain. - Author
Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet de Llobregat, Spain. - Author
Medizinische Klinik 2, Early Clinical Trial Unit, University Hospital Würzburg, Würzburg, Germany. - Author
Metronomia Clinical Research, Munich, Germany. - Author
NEXT Oncology Phase I Unit/IOB - Hospital Quirónsalud Barcelona, Barcelona, Spain. - Author
Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt am Main, Germany. - Author
START Madrid-CIOCC, Centro Integral Oncológico Clara Campal, Madrid, Spain. - Author
The University of Chicago Medical Center, Chicago, IL, USA. - Author
University Medical Center Utrecht and Princess Máxima Center, Utrecht, The Netherlands. - Author
Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d'Hebron, Barcelona, Spain. - Author
West German Cancer Center, Department of Medical Oncology, University Hospital Essen, Essen, Germany. - Author
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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.

Keywords

Zero hunger

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 1/134, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-06:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 85.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 91 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 212.5.
  • The number of mentions on the social network Facebook: 1 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 127 (Altmetric).
  • The number of mentions in news outlets: 17 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 2 - Zero hunger, with a probability of 42% according to the mBERT algorithm developed by Aurora University.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Austria; France; Germany; Netherlands; Switzerland; United States of America.