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

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

Autors: 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

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Resum

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.

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