Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti–PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.

中文翻译：

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JAK 抑制增强霍奇金淋巴瘤患者的检查点阻断免疫治疗


通过检查点抑制剂免疫疗法释放抗肿瘤 T 细胞活性对癌症患者有效，但临床反应有限。通过 Janus 激酶 (JAK) 信号转导器和转录激活剂 (STAT) 途径的细胞因子信号传导与检查点免疫治疗耐药性相关。我们报告了 JAK 抑制剂鲁索替尼 (ruxolitinib) 与抗 PD-1 抗体纳武单抗 (nivolumab) 联合治疗检查点抑制剂免疫治疗后复发或难治性霍奇金淋巴瘤患者的 I 期临床试验。该组合的最佳总体响应率为 53% (10/19)。 Ruxolitinib 显着降低了中性粒细胞与淋巴细胞的比率和骨髓抑制细胞的百分比，但增加了产生细胞因子的 T 细胞的数量。鲁索替尼挽救了耗尽的 T 细胞的功能，并增强了临床前实体瘤和淋巴瘤模型中免疫检查点阻断的功效。这种协同作用的特点是从抑制性骨髓细胞转变为免疫刺激性骨髓细胞，从而增强了 T 细胞分裂。