1. JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.
- Author
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Zak J, Pratumchai I, Marro BS, Marquardt KL, Zavareh RB, Lairson LL, Oldstone MBA, Varner JA, Hegerova L, Cao Q, Farooq U, Kenkre VP, Bachanova V, and Teijaro JR
- Subjects
- Adult, Aged, Animals, Female, Humans, Male, Mice, Middle Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Synergism, Immunotherapy, Janus Kinases metabolism, Janus Kinases antagonists & inhibitors, Programmed Cell Death 1 Receptor antagonists & inhibitors, Mice, Inbred C57BL, Mice, Inbred BALB C, Hodgkin Disease drug therapy, Hodgkin Disease immunology, Hodgkin Disease therapy, Immune Checkpoint Inhibitors therapeutic use, Janus Kinase Inhibitors therapeutic use, Nitriles therapeutic use, Nivolumab therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2024
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