JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma

  • Science. 2024 Jun 21;384(6702):eade8520. doi: 10.1126/science.ade8520.
Jaroslav Zak  1 ,  Isaraphorn Pratumchai  1  2 ,  Brett S Marro  1 ,  Kristi L Marquardt  1 ,  Reza Beheshti Zavareh  3 ,  Luke L Lairson  3 ,  Michael B A Oldstone  1 ,  Judith A Varner  4 ,  Livia Hegerova  5 ,  Qing Cao  6 ,  Umar Farooq  7 ,  Vaishalee P Kenkre  8 ,  Veronika Bachanova  #  9 ,  John R Teijaro  #  1
Affiliations
  • 1. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
  • 2. Department of Immunology, Leiden University Medical Centre, Leiden, Netherlands.
  • 3. Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 4. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
  • 5. Division of Hematology, University of Washington School of Medicine, Seattle, WA, USA.
  • 6. Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
  • 7. Division of Hematology and Oncology and Bone Marrow Transplantation, University of Iowa, Iowa City, IA, USA.
  • 8. Division of Hematology/Oncology, University of Wisconsin, Madison, WI, USA.
  • 9. Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
  • # Contributed equally.
PMID: 38900864 DOI: 10.1126/science.ade8520
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.

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