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

Publication

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

Journal Paper/Review - Dec 11, 2024

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

Citation

Melero I, de Miguel Luken M, de Velasco G, Garralda E, Martin-Liberal J, Jörger M, Alonso G, Goebeler M, Schuler M, König D, Dummer R, Reig M, Rodriguez Ruiz M, Calvo E, Esteban-Villarrubia J, Oberoi A, Sabat P, Soto-Castillo J, Koster K, Saavedra O, Sayehli C, Gromke T, Läubli H, Ramelyte E, Fortuny M, Landa-Magdalena A, Moreno I, Torres-Jiménez J, Hernando-Calvo A, Hess D, Racca F, Richly H, Schmitt A, Eggenschwiler C, Sanduzzi-Zamparelli M, Vilalta-Lacarra A, Trojan J, Koch C, Galle P, Foerster F, Trajanoski Z, Hackl H, Gogolla F, Koll F, Wild P, Chun F, Reis H, Lloyd P, Machacek M, Gajewski T, Fridman W, Eggermont A, Bargou R, Schöniger S, Rüschoff J, Tereshchenko A, Zink C, Dantas-Silva A, Lichtenegger F, Akdemir J, Rüdiger M, L'Huillier P, Dutta A, Haake M, Auckenthaler A, Gjorgjioska A, Rössler B, Hermann F, Liebig M, Reichhardt D, Schuberth-Wagner C, Wischhusen J, Fettes P, Auer M, Klar K, Leo E. Neutralizing GDF-15 can overcome anti-PD-1 and anti-PD-L1 resistance in solid tumours. Nature 2024

Type

Journal Paper/Review (English)

Journal

Nature 2024

Publication Date

Dec 11, 2024

Issn Electronic

1476-4687

Brief description/objective

Cancer immunotherapies with antibodies blocking immune checkpoint molecules are clinically active across multiple cancer entities and have markedly improved cancer treatment. Yet, response rates are still limited, and tumour progression commonly occurs. 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. 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.