Background: Pancreatic cancer will claim an estimated 47,050 lives in the USA in 2020, with an expected 5 year survival of 10%. Thus there is an urgent need for novel treatment options in this disease. We hypothesize that effective response against pancreatic cancer requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine fusion protein), and off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: The ongoing QUILT 88 phase II/III, multi-center, three-cohort, open-label, US study (NCT04390399) to evaluate the comparative efficacy and overall safety of standard-of-care chemotherapy versus standard-of-care chemotherapy in combination with aldoxorubicin HCl, N-803, and PD-L1 t-haNK in subjects with locally advanced or metastatic pancreatic cancer. Each treatment setting (ie, first line maintenance, second line, or third line or greater) will be evaluated independently as a separate cohort. Subjects with locally advanced or metastatic pancreatic cancer who have received at least 16 weeks of treatment with gemcitabine plus nab-paclitaxel, and have had either a partial response (PR), CR, or stable disease (SD), will be enrolled into Cohort A to receive first-line maintenance therapy. Subjects who have disease progression on or after receiving first-line treatment with gemcitabine plus nab-paclitaxel or another first-line chemotherapy regimen (eg, FOLFIRINOX), or who have discontinued first-line treatment (eg, due to toxicity or intolerance) will be enrolled into Cohort B to receive second-line therapy randomized to irinotecan-liposome/5FU/LV versus experimental arm. Subjects who have disease progression after receiving at least 2 lines of therapy for pancreatic cancer, will be enrolled into Cohort C to receive third-line or greater treatment. Primary endpoints by cohort are: A) PFS per RECIST V1., B & C) OS. The secondary endpoints include overall response rate, DoR, DCR, OS(cohort A) and QoL by patient-reported outcomes. Clinical trial information: NCT04390399