JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

• 成果类型: Article
• 署名作者: Zak, Jaroslav; Pratumchai, Isaraphorn; Marro, Brett S.; Marquardt, Kristi L.; Zavareh, Reza Beheshti; Lairson, Luke L.; Oldstone, Michael B. A.; Varner, Judith A.; Hegerova, Livia; Cao, Qing; Farooq, Umar; Kenkre, Vaishalee P.; Bachanova, Veronika; Teijaro, John R.
• 署名单位: Scripps Research Institute; Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; Scripps Research Institute; University of California System; University of California San Diego; University of Washington; University of Washington Seattle; University of Minnesota System; University of Minnesota Twin Cities; University of Iowa; University of Wisconsin System; University of Wisconsin Madison; University of Minnesota System; University of Minnesota Twin Cities
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9974
• DOI: 10.1126/science.ade8520
• 发表日期: 2024-06-21
• 页码: 1315-+
• 关键词: lymphocytic choriomeningitis virus; function in-vitro; cell-function; preclinical characterization; kinase inhibitor; ruxolitinib; neutrophil; interferon; infection; resistance

摘要

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.