Background: Pancreatic cancer claimed an estimated 47,050 lives in the USA in 2020, with an expected median overall survival (OS) of 3 months in 3rd line. (Manax ASCO GI 2019), with no evidence of disease control in these late stage patients. We hypothesize that effective response against pancreatic cancer requires orchestration of both the innate and adaptive immune system to accomplish immunogenic cell death with survival benefit. Herein we report the first results of a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine superagonist), and allogeneic off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: We report data from a multi-center study, on 55 3rd line or greater, subjects treated with low dose, chemo radiation Nab-paclitaxel (100 mg/ m2 IV), Gemcitabine (600 mg/m2 IV); Cyclophosphamide (50 mg PO BID) and low dose SBRT. This induction immuno-modulation therapy to induce DAMPs was followed with investigational agents activating the innate and adaptive systems: Aldoxorubicin (150 mg/m2 IV), N-803, an IL-15 superagonist (15 μg/kg SC) and PD-L1 t-haNK (̃2 × 109cells/dose IV). Prophylactic G-CSF or EPO was not allowed. All treatments were administered on an outpatient basis. Results: As of submission, median follow-up is 3.9 months. Median age 62, M:F ratio 35:20. ECOG 0-1,92%. 41/55 (75%) subjects reported a grade ≥3 AE related to the chemo radiation, anemia 44%, neutropenia 24%, thrombocytopenia 11%, all others < 10%. SAEs attributed to investigational agents were reported in 5/55 (9%) patients. Of the 44 patients evaluable at 3 months to date, the OS is 81.8% (36/44), 95% CI: 67.3%, 91.8%. The disease control rate of 47 evaluable patients is 36.2% (17/47) 95% CI 22.7%,51.5%. No treatment related deaths have occurred. Treatment is ongoing for 16 subjects, with 14 months as the longest duration on therapy to date. Median OS not yet reached with 28/55 alive to date. Median PFS is 2.4 months (95% CI: 2.0, 3.7) and 36% of subjects not having progressed to date. Conclusions: Historical 3 month median OS in 3rd line metastatic pancreatic cancer patients has been exceeded. Early safety and promising efficacy is seen in QUILT 88 investigating a novel combination immunotherapy protocol of low-dose chemoradiation, N-803 and PDL1 t-haNK therapy. Updated data will be presented. Clinical trial information: NCT04390399.