%0 Journal Article
%T JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.
%A Zak J
%A Pratumchai I
%A Marro BS
%A Marquardt KL
%A Zavareh RB
%A Lairson LL
%A Oldstone MBA
%A Varner JA
%A Hegerova L
%A Cao Q
%A Farooq U
%A Kenkre VP
%A Bachanova V
%A Teijaro JR
%J Science
%V 384
%N 6702
%D 2024 Jun 21
%M 38900864
%F 63.714
%R 10.1126/science.ade8520
%X 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.