JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma
Mené sur des patients atteints d'un lymphome hodgkinin récidivant ou réfractaire, cet essai de phase I/II évalue l'efficacité, du point de vue du taux de réponse globale, de l'ajout du ruxolitinib (un inhibiteur de JAK) au nivolumab, après l'échec d'une immunothérapie par inhibiteur de point de contrôle immunitaire
INTRODUCTION: Checkpoint immunotherapy has revolutionized cancer treatment in the past decade for many cancer patients. Despite durable responses in some patients, many either fail to respond or develop resistance to the current immunotherapy regimens. Thus, a substantial unmet clinical need remains in nonresponsive patients to reinvigorate checkpoint immunotherapy responses. RATIONALE: T cell exhaustion limits current responses to immunotherapy. Using the results of a high-throughput screen for small molecules reversing T cell exhaustion, we explored the hypothesis that a small molecule could enhance antitumor T cell responses and improve the efficacy of immune checkpoint inhibitor (ICI) immunotherapy in cancer. RESULTS: Following the screening of the ReFrame library in the lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13) model of immune suppression, we identified a preponderance of Janus kinase inhibitors (JAKis), which could dramatically rescue the function of exhausted T cells. Using the first clinically approved JAKi, ruxolitinib, we demonstrated that, rather than suppress the immune response, JAK inhibition could enhance T and NK cell numbers and function in Cl13 as well as syngeneic tumor models and enhance tumor control in combination with ICI immunotherapy. Notably, this combination was effective in multiple solid tumor and lymphoma models, including those without prior ICI resistance and those in which ruxolitinib monotherapy had no effect on tumor growth. Treatment of both Cl13-infected and tumor-bearing mice with JAKis also modulated the transcriptomic and functional properties of myeloid cells from an immune suppressive state to one with immune-stimulatory potential. The ability of ruxolitinib to enhance checkpoint inhibitor efficacy was conditional on the presence of myeloid cells, and myeloid cells in ruxolitinib and ICI–treated mice showed upregulation of antigen presentation molecules, including major histocompatibility complex class II (MHC-II). These results demonstrate that ruxolitinib’s ability to enhance antitumor T cell responses is partly T cell extrinsic and dependent on myeloid cell modulation. We report the results of a phase I clinical trial in patients with Hodgkin lymphoma who relapsed or were refractory after prior checkpoint inhibitor immunotherapy. Ruxolitinib was administered in combination with nivolumab. The combination yielded a best overall response rate of 53% with 6/19 patients achieving a complete metabolic response to therapy. Clinical response correlated with reductions in neutrophil-to-lymphocyte ratios (NLRs), percentages of suppressive myeloid cells, and increases in the numbers of cytokine-producing T cells after ruxolitinib treatment. In both preclinical models and patient samples, the transcriptomic signature of granulocyte colony-stimulating factor (G-CSF) (a JAK-dependent cytokine) signaling was significantly down-regulated by ruxolitinib, suggesting that ruxolitinib may prevent suppressive programming of myeloid cells owing to excessive JAK–signal transducer and activator of transcription (STAT) signaling by cytokines such as G-CSF. CONCLUSION: Our results support the therapeutic potential of small-molecule JAK inhibition in combination with checkpoint inhibitors in cancer. We demonstrate that JAK inhibition is not immune suppressive but rather stimulatory, suggesting that the context of JAK inhibitor usage dictates the ultimate treatment outcome. Given that the immunomodulatory properties and clinical efficacy were not exclusive to Hodgkin lymphoma, it will be important to explore the clinical potential of JAK inhibitors with ICI in solid tumors, particularly those in which suppressive myeloid cells correlate with poor response to ICI monotherapy.