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TPS9139 Background: Although tumor microenvironments may contain chronic inflammatory cells, this milieu can lead to immune evasion and may contribute to resistance to immunotherapy. Dendritic cells are one of the most potent cross presenters of tumor antigen, and their function is crucial to tumor-directed adaptive immune responses. In the KP mouse model of lung adenocarcinoma (KrasG12D; Tp53-/-), we recently identified interleukin-4 (IL-4)-driven suppression of tumor-antigen charged dendritic cells, which was similarly seen in human lung cancer lesions (Maier, B., et al., A conserved dendritic-cell regulatory program limits antitumour immunity. Nature, 2020.580[7802]:257-262). In the mouse model IL-4 blockade resulted in an increase in IL-12, IFNg and TNF in CD8+ T cells and decreased tumor burden, and further antitumor activity was seen when combined with PD-L1 blockade. Dupilumab is a fully human monoclonal antibody that blocks the IL-4 receptor alpha subunit which disrupts signaling through receptors for both IL-4 and IL-13; it is FDA approved for patients with multiple atopic conditions, in whom series adverse effects are rare. Based on this pre-clinical data, we hypothesize that the addition of dupilumab to anti PD-(L)1 therapy will be well tolerated, and will rescue the anti-tumor effect of immune checkpoint blockade. Methods: This is a phase Ib/II trial. Patients with relapsed/refractory NSCLC who have received prior anti PD-(L)1 treatment are eligible for enrollment. In a phase Ib safety run-in, six patients will be enrolled in a modified set-dose 3+3 design. If no more than 1 DLT is observed during this phase, the trial will proceed to phase II. Phase II will enroll a further 15 patients in a minimax design with early stopping for futility to a maximum total of 21 patients. Patients will undergo pre-treatment biopsies and peripheral blood sampling prior to receiving 3 doses of dupilumab, administered every three weeks, in conjunction with continuing standard-of-care anti-PD-(L)1 therapy. Patients will undergo repeat biopsies 4 weeks after starting therapy. After completion of dupilumab (at 9 weeks) patients will undergo repeat staging. The primary endpoint of phase 1b is safety as measured by frequency and severity of adverse effects. The primary endpoint of phase II is overall response rate as assessed using RECIST 1.1 criteria at the time of post-dupilumab imaging. Exploratory endpoints include analysis of peripheral blood by CyTOF and O-link, and tissue biopsies will be analyzed by multiplex-IHC and bulk-RNA-sequencing. T cell receptor sequencing will be performed on tumor and matched peripheral blood samples, and circulating tumor DNA will be assessed at multiple time points. Phase 1b is currently enrolling as planned. Clinical trial information: NCT05013450.