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

作者：Divij Mathew, Melina Elpi Marmarelis, Caitlin M. Foley, Joshua Michael Bauml, Darwin Ye, Reem Ghinnagow, Shin Foong Ngiow, Max Klapholz, Soyeong Jun, Zhaojun Zhang, Robert Zorc, Christiana W. Davis, Maximillian Diehn, Josephine Ruth Giles, Alexander Chan Chi Huang, Wei‐Ting Hwang, Nancy R. Zhang, Adam Jacob Schoenfeld, Erica L. Carpenter, Corey Jay Langer, E. John Wherry, Andy J. Minn · 发表于：Science · 年份：2024 · DOI：10.1126/science.adf1329 · 被引用次数：231 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

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.