%0 Journal Article
%T Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients.
%A Mathew D
%A Marmarelis ME
%A Foley C
%A Bauml JM
%A Ye D
%A Ghinnagow R
%A Ngiow SF
%A Klapholz M
%A Jun S
%A Zhang Z
%A Zorc R
%A Davis CW
%A Diehn M
%A Giles JR
%A Huang AC
%A Hwang WT
%A Zhang NR
%A Schoenfeld AJ
%A Carpenter EL
%A Langer CJ
%A Wherry EJ
%A Minn AJ
%J Science
%V 384
%N 6702
%D 2024 Jun 21
%M 38900877
%F 63.714
%R 10.1126/science.adf1329
%X 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.