Background: Pancreatic cancer is the third leading cause of cancer-related deaths in the US. Patients who relapse after first/second-line chemotherapy have a 2 month median survival. In this relapsed population, there is no approved therapy. Effective response requires a coordinated approach that orchestrates both the innate and adaptive immune system. We hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with clinical benefit. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf allogeneic high-affinity NK cell infusion (haNK). We report the first complete response (CR) to an NK-based immunotherapy combination in pancreatic cancer. Methods: QUILT-3.039/3.060/3.070/3.080 enrolled a total of 12 patients (8M/4F), median age 57.5 (35-74), ECOG 0-2) with advanced pancreatic with progressive disease after prior chemotherapy. There were differences in the dose and schedule of agents used across the various protocols. Common elements were: 1. Reduced dose metronomic chemotherapy (combinations of aldoxorubicin, gemcitabine, abraxane, oxaliplatin, 5FU, and cyclophosphamide) 2. SBRT, 3. Avelumab, 4. N803 (IgG1 Fc-engineered IL-15-fusion protein), 5. Allogeneic haNK cells. This experience led to a SPIND substituting allogeneic haNK cells with allogeneic haNK cells targeted against PDL-1. All treatment was in an outpatient setting. A median of 6 cycles of haNK cells (2-15) were delivered for a cumulative median dose of 29.0 x 10⁹ cells per patient (8.0-56.0 x 10⁹). Results: In 12 patients across 4 studies, a median of 6 (2,15) cycles of treatment were delivered, resulting in median PFS of 6.6 mo (3.3-12.4), OS 8.1 mo (5.0-27.0). 11/12 (92%) patients experienced stable disease (SD) for > 8 weeks. 11/12 (92%) also experience at least 1 grade 3 AE: neutropenia (92%), anemia (50%), febrile neutropenia (17%), diarrhea (8%), hyperglycemia (25%), hyponatremia (17%), and elevated alkaline phosphatase (8%). The SPIND patient (79 yo M, ECOG 1) received 7 cycles and achieved a CR by PET with 5 months follow-up to date. No grade 4 AEs were seen. No severe immune related AE’s were seen. Conclusions: Orchestrated immunomodulatory outpatient combination treatment is feasible and results in clinical benefit and CR in selected patients with acceptable toxicity.