Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients Journal Article
| Authors: | Mathew, D.; Marmarelis, M. E.; Foley, C.; Bauml, J. M.; Ye, D.; Ghinnagow, R.; Ngiow, S. F.; Klapholz, M.; Jun, S.; Zhang, Z.; Zorc, R.; Davis, C. W.; Diehn, M.; Giles, J. R.; Huang, A. C.; Hwang, W. T.; Zhang, N. R.; Schoenfeld, A. J.; Carpenter, E. L.; Langer, C. J.; Wherry, E. J.; Minn, A. J. |
| Article Title: | Combined JAK inhibition and PD-1 immunotherapy for non-small cell lung cancer patients |
| 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. |
| Keywords: | janus kinase inhibitor; clinical trial; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; animals; mice; phase 2 clinical trial; carcinoma, non-small-cell lung; lung neoplasms; lung tumor; immunology; immunotherapy; drug therapy; therapy; programmed death 1 receptor; non small cell lung cancer; janus kinase 1; immune checkpoint inhibitor; humans; human; female; pdcd1 protein, human; programmed cell death 1 receptor; immune checkpoint inhibitors; janus kinase inhibitors; jak1 protein, human |
| Journal Title: | Science |
| Volume: | 384 |
| Issue: | 6702 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2024-06-21 |
| Start Page: | eadf1329 |
| Language: | English |
| DOI: | 10.1126/science.adf1329 |
| PUBMED: | 38900877 |
| PROVIDER: | scopus |
| PMCID: | PMC11327955 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
