研究人员报告了一项Janus激酶（JAK）抑制剂鲁索利替尼联合抗PD-1抗体纳武单抗治疗霍奇金淋巴瘤患者的I期临床试验。联合治疗的最佳总反应率为53%（10/19）。鲁索利替尼能显著降低中性粒细胞与淋巴细胞的比例以及骨髓抑制细胞的百分比，但能增加产生细胞因子的T细胞的数量。
在临床前实体瘤和淋巴瘤模型中，鲁索利替尼能挽救衰竭T细胞的功能，增强免疫检查点阻断的疗效。这种协同作用的特点是从抑制性髓系细胞转向免疫刺激性髓系细胞，从而增强了T细胞的分裂。
据悉，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JAK-信号转导和激活转录（STAT）通路的细胞因子信号与检查点免疫疗法的耐药性相关。
附：英文原文
Title: JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma
Author: Jaroslav Zak, Isaraphorn Pratumchai, Brett S. Marro, Kristi L. Marquardt, Reza Beheshti Zavareh, Luke L. Lairson, Michael B. A. Oldstone, Judith A. Varner, Livia Hegerova, Qing Cao, Umar Farooq, Vaishalee P. Kenkre, Veronika Bachanova, John R. Teijaro
Issue&Volume: 2024-06-21
Abstract: 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.
DOI: ade8520
Source: https://www.science.org/doi/10.1126/science.ade8520