Inclusion Criteria:

• Histologically confirmed pancreatic adenocarcinoma with vascular involvement, either borderline/potentially resectable or locally advanced.
• Borderline resectable is defined by the NCCN as tumors (based on cross sectional imaging) with venous involvement of the SMV/portal vein demonstrated tumor abutment with or without impingement and narrowing of the lumen, either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection or reconstruction; gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis; or tumor abutment of the SMA not to exceed greater than 180 degrees of the circumference of the vessel wall. Tumors involving retroperitoneal structures that can be surgically removed (i.e., kidney), will also be included.
• Locally advanced unresectable disease is defined by the NCCN as: Tumors of the head that have greater than 180 degrees of SMA encasement or any celiac abutment, unreconstructable SMV or portal occlusion, or aortic invasion or encasement. Tumors of the body with SMA or celiac encasement of greater than 180 degrees, unreconstructable SMV or portal occlusion, or aortic invasion. Tumors of the tail with SMA or celiac encasement of greater than 180 degrees. Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field are deemed unresectable.
• Age ≥ 18 years old.
• ECOG Performance Status 0-1.
• Previous completion of at least three (3) months of EITHER gemcitabine plus nab-paclitaxel OR FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan and leucovorin)
• Previous completion of either stereotactic-body radiation therapy (SBRT) (minimum 24 Gy) or external beam irradiation (EBRT) (minimum 45 Gy or 36 Gy in 15 fractions).
• Participation in any investigational drug study within 4 weeks preceding the start of study treatment is PERMITTED.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months after IORT.
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after IORT. Women who are not of childbearing potential; i.e., who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Evidence of disease progression or distant metastases.
• Pregnant or lactating women.
• Treatment for other invasive carcinomas within the last five years who are at greater than 5% risk of recurrence at time of eligibility screening. Carcinoma in-situ and basal cell carcinoma/ squamous cell carcinoma of the skin are allowed.
• Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• An active infection requiring systemic therapy.
• Other serious medical conditions that the investigator feels might compromise study participation.