德国CatalYm公司Eugen Leo等研究人员合作发现，中和GDF-15可以克服实体肿瘤中抗PD-1和抗PD-L1治疗的耐药性。该项研究成果于2024年12月11日在线发表在《自然》杂志上。

研究人员表示，抗免疫检查点分子阻断抗体的癌症免疫疗法在多种癌症类型中具有临床活性，并显著改善了癌症治疗。然而，疗效仍然有限，且肿瘤进展通常发生。肿瘤微环境中的可溶性和细胞结合因子对癌症免疫有负面影响。

近期发现，生长分化因子15（GDF-15）是一种由多种癌症类型大量产生的细胞因子，能够干扰抗肿瘤免疫反应。在临床前癌症模型中，GDF-15的阻断与抗PD-1介导的检查点抑制治疗具有协同效应，增强了其疗效。

在一项首次人体I期–IIa期临床试验（GDFATHER-1/2a试验，NCT04725474）中，研究人员针对抗PD-1或抗PD-L1疗法耐药的晚期癌症患者（通常称为抗PD-1/PD-L1耐药）使用了中和GDF-15抗体visugromab（CTL-002），并与抗PD-1抗体nivolumab联合治疗。

研究人员展示了，在一些非鳞状非小细胞肺癌和尿路上皮癌患者中获得了持久且深度的反应，这两种癌症类型在“癌症基因组图谱”数据库中，对约10000个肿瘤样本的体外筛选中被发现常常受到GDF-15的免疫抑制作用。在治疗反应中，研究人员观察到肿瘤浸润、细胞增殖、与干扰素-γ相关的信号通路和细胞毒性T细胞的颗粒酶B表达增加。中和GDF-15有望克服癌症中免疫检查点抑制的耐药性。

附：英文原文

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

Author: Melero, Ignacio, de Miguel Luken, Maria, de Velasco, Guillermo, Garralda, Elena, Martn-Liberal, Juan, Joerger, Markus, Alonso, Guzman, Goebeler, Maria-Elisabeth, Schuler, Martin, Knig, David, Dummer, Reinhard, Reig, Maria, Rodriguez Ruiz, Maria-Esperanza, Calvo, Emiliano, Esteban-Villarrubia, Jorge, Oberoi, Arjun, Sabat, Paula, Soto-Castillo, Juan Jos, Koster, Kira-Lee, Saavedra, Omar, Sayehli, Cyrus, Gromke, Tanja, Lubli, Heinz, Ramelyte, Egle, Fortuny, Marta, Landa-Magdalena, Ana, Moreno, Irene, Torres-Jimnez, Javier, Hernando-Calvo, Alberto, Hess, Dagmar, Racca, Fabricio, Richly, Heike, Schmitt, Andreas M., Eggenschwiler, Corinne, Sanduzzi-Zamparelli, Marco, Vilalta-Lacarra, Anna, Trojan, Jrg, Koch, Christine, Galle, Peter R., Foerster, Friedrich, Trajanoski, Zlatko, Hackl, Hubert, Gogolla, Falk, Koll, Florestan J., Wild, Peter, Chun, Felix Kyoung Hwan, Reis, Henning, Lloyd, Peter, Machacek, Matthias, Gajewski, Thomas F., Fridman, Wolf H., Eggermont, Alexander M. M., Bargou, Ralf, Schniger, Sandra, Rschoff, Josef, Tereshchenko, Anastasiia, Zink, Carina, da Silva, Antonio, Lichtenegger, Felix S., Akdemir, Julia, Rdiger, Manfred, LHuillier, Phil, Dutta, Aradhana, Haake, Markus, Auckenthaler, Alexandra, Gjorgjioska, Ana, Rssler, Bernhard, Hermann, Frank, Liebig, Mara, Reichhardt, Daniela, Schuberth-Wagner, Christine

Issue&Volume: 2024-12-11

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 granzymeB expression by cytotoxic Tcells were observed in response to treatment. Neutralizing GDF-15 holds promise in overcoming resistance to immune checkpoint inhibition in cancer.

DOI: 10.1038/s41586-024-08305-z

Source: https://www.nature.com/articles/s41586-024-08305-z