Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients
Science, 2024
Mathew D., Marmarelis M., Foley C., Bauml J., Ye D., Ghinnagow R., Ngiow S., Klapholz M., Jun S., Zhang Z., Zorc R., Davis C., Diehn M., Giles J., Huang A., Hwang W., Zhang N., Schoenfeld A., Carpenter E., Langer C., Wherry E., Minn A.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Oncology Immunotherapy | Pathophysiology | Plasma | Olink Target 96 |
Abstract
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.