Durable Response and Improved CD8 T Cell Plasticity in Lung Cancer Patients After PD1 Blockade and JAK Inhibition
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.; Diehn, M.; Hwang, W.-T.; Zhang, N. R.; Langer, C. J.; Wherry, E. J.; Minn, A. J.
Show abstract
Persistent inflammation including type-one interferon (IFN-I) can cause immunosuppression. We show that delayed administration of the JAK1 inhibitor itacitinib after anti-PD1 improves immune function and anti-tumor response in mice, and results in high response rates (67%) in a phase-2 clinical trial for metastatic non-small cell lung cancer with tumor PDL1[≥]50%. In contrast to patients with low inflammation who responded to anti-PD1, patients with elevated inflammation had poor immune and tumor responses to anti-PD1 that improved after adding itacitinib. Itacitinib promoted features of CD8 T cell plasticity and therapeutic responses of exhausted and effector-memory clonotypes. Patients with persistent IFN-I signaling refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve anti-PD1 efficacy by pivoting T cell differentiation dynamics.
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