Background: Treatment of LAUPC most commonly involves chemotherapy +/- RT. Patients(pts) who can be downstaged and undergo R0 resection have significant improvement in overall survival, but conventional chemoRT converts < 10% of patients with LAUPC. If the effects of RT can be augmented then higher R0 resection rates may be achieved and improve survival. In pre-clinical models, RT leads to increased expression of M-CSF from pancreatic tumor cells and marked immune suppression within the tumor microenvironment via expansion of tumor associated macrophages (TAMs). Concurrent blockade of M-CSF with RT reduces TAM infiltration, prevents the generation of tumor promoting T cell populations, and increases the therapeutic effect of RT. RT also induces up-regulation of PD-L1 in TAMs, another mode of immune suppression that can account for RT resistance in LAUPC. (Seifert et al. 2016). These data suggest the efficacy of RT in LAUPC is limited by its promotion of innate and adaptive immune suppression. CSF1R blockade with Cabira combined with PD-1 blockade with Nivo may enhance the efficacy of SBRT by reprogramming the TAM compartment in tumors, thereby preventing an immune suppressive phenotype and augmenting T-cell mediated anti-tumor response. Methods: Single arm phase II study designed to evaluate safety, tolerability, and surgical resection rate in LAUPC pts treated with concurrent Nivo, Cabira, and SBRT. Exploratory endpoints include immune changes within blood and tissue following treatment and correlation with clinical endpoints. Key eligibility: completion of 2- 6 months standard induction chemotherapy, normal organ and marrow function, pre- and on-treatment biopsy, and PS ≤ 1. Following initial biopsy and placement of fiducials, Cabira 4mg/kg and Nivo 240mg are given D1 of every 14 day cycle. SBRT 6.6 Gy x 5 consecutive fractions starts D8. After 2 cycles, repeat biopsy and imaging is performed. Treatment with Cabira and Nivo continues every 2 weeks and imaging is done every 8 weeks, at which time pt is assessed for surgical resection. If pt is downstaged, treatment is discontinued and pt proceeds to surgery. Preliminary 6 pt safety cohort is monitored for unacceptable toxicities. If < 3 unacceptable toxicities in the first 6 subjects enrolled, then plan for expansion phase with 14 more pts. As of abstract submission, 3 pts have been enrolled. Clinical trial information: NCT03599362