Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours PMID: 39663448

ADC Targets in Oncology

2026-04-10

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

1. Clínica Universidad de Navarra, CIMA, IDISNA and CIBERONC, Pamplona, Spain. [email protected].
2. Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
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. [email protected].

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.