JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

• DOI: 10.1126/science.ade8520
• Publication Date: 2024-06-20T17:59:48Z
• Authors: Jaroslav Zak; Isaraphorn Pratum...; Brett S. Marro; Kristi L. Marquardt; Reza Beheshti Zav...; Luke L. Lairson; Michael B. A. Old...; Judith A. Varner; Livia Hegerova; Qing Cao; Umar Farooq; Vaishalee P. Kenkre; Veronika Bachanova; John R. Teijaro
• Keywords: Adult; Male; 0301 basic medicine; Lymphatic Research; Lymphoma; General Science & Technology; T-Lymphocytes; Oncology and Carcinogenesis; Immunology; Programmed Cell Death 1 Receptor; 610; Inbred C57BL; Vaccine Related; Mice; 03 medical and health sciences; Rare Diseases; 616; Antineoplastic Combined Chemotherapy Protocols; Nitriles; Animals; Humans; Janus Kinase Inhibitors; Minority Health; Immune Checkpoint Inhibitors; Inbred BALB C; Cancer; Aged; Janus Kinases; Biomedical and Clinical Sciences; Drug Synergism; Hematology; Middle Aged; Hodgkin Disease; Health Disparities; Orphan Drug; Nivolumab; Pyrimidines; 5.1 Pharmaceuticals; 6.1 Pharmaceuticals; Pyrazoles; Immunization; Female; Immunotherapy

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.