Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients

• 成果类型: Article
• 署名作者: Mathew, Divij; Marmarelis, Melina E.; Foley, Caitlin; Bauml, Joshua M.; Ye, Darwin; Ghinnagow, Reem; Ngiow, Shin Foong; Klapholz, Max; Jun, Soyeong; Zhang, Zhaojun; Zorc, Robert; Davis, Christiana W.; Diehn, Maximillian; Giles, Josephine R.; Huang, Alexander C.; Hwang, Wei-Ting; Zhang, Nancy R.; Schoenfeld, Adam J.; Carpenter, Erica L.; Langer, Corey J.; Wherry, E. John; Minn, Andy J.
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Stanford University; Stanford Cancer Institute; Stanford University; University of Pennsylvania; University of Pennsylvania; Memorial Sloan Kettering Cancer Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9973
• DOI: 10.1126/science.adf1329
• 发表日期: 2024-06-21
• 页码: 1314-+
• 关键词: cd8(+) t-cells; in-vivo; blockade; proliferation; pembrolizumab; resistance; mutations; landscape; infection; subsets

摘要

Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti-PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD-1 immunotherapy by pivoting T cell differentiation dynamics.