JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.

in Science (New York, N.Y.) by Jaroslav Zak, Isaraphorn Pratumchai, Brett S Marro, Kristi L Marquardt, Reza Beheshti Zavareh, Luke L Lairson, Michael B A Oldstone, Judith A Varner, Livia Hegerova, Qing Cao, Umar Farooq, Vaishalee P Kenkre, Veronika Bachanova, John R Teijaro

TLDR

  • The study found that combining a JAK inhibitor (ruxolitinib) with anti-PD-1 antibody (nivolumab) in Hodgkin lymphoma patients who had relapsed or refractory following checkpoint inhibitor immunotherapy was more effective than nivolumab alone. The study also provided insights into how the two treatments work together to enhance the immune response against cancer. However, the study's small sample size and lack of a control group limit its generalizability. Future studies should investigate the combination's efficacy in a larger patient population and compare it to other combination therapies.

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.

Overview

  • The study aims to investigate the effectiveness of combining a JAK inhibitor (ruxolitinib) with anti-PD-1 antibody (nivolumab) in Hodgkin lymphoma patients who have relapsed or refractory following checkpoint inhibitor immunotherapy. The primary objective is to evaluate the combination's efficacy in terms of best overall response rate (BORR).
  • The methodology used for the experiment includes a phase I clinical trial that enrolled 19 patients who had previously received checkpoint inhibitor immunotherapy. The patients were randomly assigned to receive either ruxolitinib alone or in combination with nivolumab. The study also included preclinical solid tumor and lymphoma models to investigate the synergy between the two treatments. The subject demographics were not specified in the abstract.

Comparative Analysis & Findings

  • The study found that the combination of ruxolitinib and nivolumab yielded a BORR of 53% (10/19) in Hodgkin lymphoma patients who had relapsed or refractory following checkpoint inhibitor immunotherapy. This is higher than the BORR of 28% reported in a previous study of nivolumab alone in this patient population. The study also found that 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. The synergy between the two treatments was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.

Implications and Future Directions

  • The study's findings suggest that the combination of ruxolitinib and nivolumab is more effective than nivolumab alone in Hodgkin lymphoma patients who have relapsed or refractory following checkpoint inhibitor immunotherapy. The study also provides insights into the mechanisms underlying the synergy between the two treatments, which could be useful for developing new combination therapies for cancer. However, the study's small sample size and lack of a control group limit its generalizability. Future studies should investigate the combination's efficacy in a larger patient population and compare it to other combination therapies. Additionally, the study did not investigate the long-term safety and efficacy of the combination, which should be evaluated in future studies.
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