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.

使用阻断免疫检查点分子的抗体的癌症免疫疗法在多种癌症实体中具有临床活性，并显著改善了癌症治疗¹。然而，反应率仍然有限，并且通常会发生肿瘤进展²。肿瘤微环境中的可溶性和细胞结合因子会对癌症免疫产生负面影响。最近，生长分化因子 15 （GDF-15） 是一种由许多癌症类型大量产生的细胞因子，被证明会干扰抗肿瘤免疫反应。在临床前癌症模型中，GDF-15 阻断协同增强了抗 PD-1 介导的检查点抑制的疗效³。在一项首次人体 1-2a 期研究（GDFATHER-1/2a 试验，NCT04725474）中，抗 PD-1 或抗 PD-L1 治疗难治性晚期癌症患者（通常称为抗 PD-1/PD-L1 难治性）接受中和 抗 GDF-15 抗体 visugromab （CTL-002） 联合抗 PD-1 抗体纳武利尤单抗治疗。在这里，我们表明，在一些非鳞状非小细胞肺癌和尿路上皮癌患者中实现了持久和深入的反应，这两种癌症实体在癌症基因组图谱数据库中对大约 10,000 个肿瘤样本进行计算机模拟筛选，被鉴定为经常被 GDF-15 免疫抑制。观察到治疗后细胞毒性 T 细胞的肿瘤浸润、增殖、干扰素γ相关信号传导和颗粒酶 B 表达水平增加。中和 GDF-15 有望克服癌症对免疫检查点抑制的耐药性。