Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients
Mené sur des patients atteints d'un cancer du poumon à petites cellules de stade métastatique, cet essai de phase II évalue l'efficacité, du point de vue du taux de réponse globale et de la survie sans progression, d'un traitement de première ligne combinant itacitinib (un inhibiteur de JAK) et pembrolizumab
Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti–PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non–small cell lung cancer. Patients who failed to respond to initial anti–PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti–PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory–like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti–PD-1 immunotherapy by pivoting T cell differentiation dynamics. Cancer immunotherapy is a type of treatment that mobilizes a patient’s immune system to kill tumor cells. It has been successful in treating certain tumors, but patients frequently have chronic inflammation and immunosuppression, which can limit treatment response. Two independent clinical trials looked at whether dialing down inflammation using drugs called JAK inhibitors could improve the efficacy of anti–PD-1 immunotherapy in cancer patients (see the Perspective by Gadina and O’Shea). Mathew et al. conducted a phase 2 trial to investigate the drug combination as a first-line therapy for metastatic non-small-cell lung cancer. Delayed administration of itacitinib after treatment with pembrolizumab improved therapeutic response. Zak et al. performed a phase 1/2 trial in patients with relapsed/refractory Hodgkin’s lymphoma. A combination of ruxolitinib and nivolumab resulted in improved clinical efficacy in patients who had previously failed checkpoint blockade immunotherapy. —Priscilla N. Kelly
https://www.science.org/doi/abs/10.1126/science.adf1329 2023