Checkpoint immunotherapy has dramatically changed cancer treatment over the past decade, but many patients do not respond or develop resistance to these therapies. Recent research indicates that JAK inhibitors (JAKis), particularly ruxolitinib, may reinvigorate immune responses in these nonresponsive patients.
T cell exhaustion is a significant barrier to the effectiveness of immunotherapy. Researchers used a high-throughput screening of the ReFrame library to identify small molecules that could reverse T cell exhaustion. This led to the discovery that JAKis, especially ruxolitinib, could enhance the function of exhausted T cells.
In mouse models of immune suppression and cancer, ruxolitinib was found to boost T and NK cell numbers and function. This enhanced the efficacy of immune checkpoint inhibitors (ICIs) in controlling tumour growth, including in solid tumour and lymphoma models where prior ICI resistance was noted.
Ruxolitinib also modulated myeloid cells from an immune suppressive to an immune-stimulatory state. This myeloid cell modulation was crucial for the enhanced antitumor response. The presence of myeloid cells was necessary for ruxolitinib to improve checkpoint inhibitor efficacy, with upregulation of antigen presentation molecules like MHC-II observed.
A phase I clinical trial in Hodgkin lymphoma patients who were refractory to prior immunotherapy showed promising results. The combination of ruxolitinib and nivolumab resulted in a 53% overall response rate, with six out of 19 patients achieving a complete metabolic response. Clinical responses were associated with reduced neutrophil-to-lymphocyte ratios and suppressive myeloid cells, and increased cytokine-producing T cells.
These findings suggest that JAK inhibition, in combination with checkpoint inhibitors, holds significant therapeutic potential. Further exploration in solid tumors is warranted, particularly where suppressive myeloid cells hinder ICI monotherapy efficacy.
Helena Bradbury, EMJ
Reference
Zak J et al. JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma. Science. 2024;384(6702).
