Pressure Enabled Intrapancreatic Delivery of SD-101 With Checkpoint Blockade for Locally Advanced Pancreatic Adenocarcinoma

Inclusion Criteria: * Patients ≥18 years of age with histologically or cytologically confirmed evaluable or measurable locally advanced unresectable PDAC, or previously confirmed disease in the absence of a documented complete pathologic response. * Performance status score of 0 or 1 on the ECOG PS scale (scores range from 0 to 5, with higher numbers reflecting greater disability) * Suitable venous anatomy on a standard portal venous phase imaging as defined by absence of portal, splenic, or superior mesenteric vein complete occlusion Note: As long as there is not complete occlusion and the Interventional Radiologist confirms that the target vein can be accessed, patients may be suitable for enrollment. All 3 veins do not have to be patent for eligibility. * Having received standard of care chemoradiation therapy or a systemic chemotherapy regimen without a complete radiographic response. Standard of care chemotherapy includes gemcitabine + nab-paclitaxel, or FOLFIRINOX; for others discuss with medical monitor. Radiation with or without concurrent chemotherapy is also acceptable as a standard of care regimen * Able to understand the study and provide written informed consent prior to any study procedures * Has not received prior cytotoxic chemotherapy or targeted therapy within 14 days, or external radiation therapy within 4 weeks prior to screening * Low-burden, asymptomatic metastatic disease permitted if: 1. Metastatic disease poses no imminent threat to the patient 2. Patient is otherwise asymptomatic with respect to metastases 3. Metastases are limited to liver, lung, and/or bone 4. No single lesion greater than 5 cm 5. Less than 5 metastatic lesions total 6. No brain or peritoneal metastases Pancreatic disease must be the dominant determinant of the patient's prognosis and clinical course * Has no prior history of or other concurrent malignancy unless the malignancy is clinically insignificant, no ongoing treatment is required, and the patient is clinically stable * Has a life expectancy of \>3 months at screening as estimated by the Investigator * Has a QTc interval ≤480 msec * All associated clinically significant (in the judgment of the Investigator) drug-related toxicity from previous cancer therapy must be resolved (to Grade ≤1 or the patient's pretreatment level) prior to study treatment administration (Grade 2 alopecia, grade 2 peripheral neuropathy from prior chemotherapy, and endocrinopathies controlled on replacement therapy are allowed). * Has adequate organ function at screening as evidence by: 1. Platelet count \>80,000/μL 2. Hemoglobin ≥8.0 g/dL 3. White blood cell (WBC) count \>2,000/μL 4. Serum creatinine ≤2.0 mg/dL unless the measured creatinine clearance is ≥30 mL/min calculated by Cockcroft-Gault formula. 5. Total and direct bilirubin ≤2.0 × the upper limit of normal (ULN) and alkaline phosphatase ≤5 × ULN. For patients with documented Gilbert's disease, total bilirubin up to 3.0 mg/dL is allowed. 6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤5 × ULN 7. Amylase and lipase ≤3 × ULN 8. Prothrombin time/International Normalized Ratio (INR) or activated partial thromboplastin time (aPTT) test results at screening ≤1.5 × ULN (this applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose for at least 4 weeks prior to the first dose of study intervention) Note: Laboratory tests with exclusionary results judged by the Investigator as not compatible with the patient's clinical status may be repeated once for eligibility purposes. * Females of childbearing potential must be nonpregnant and nonlactating, or post-menopausal, and have a negative serum human chorionic gonadotropin (hCG) pregnancy test result at screening and prior to the first dose of study intervention. 1. Females of childbearing potential must agree to abstain from sexual activity with nonsterilized male partners, or if sexually active with a nonsterilized male partner must agree to use highly effective methods of contraception from screening, throughout the study and agree to continue using such precautions for 100 days after the final dose of study intervention. 2. Nonsterilized males who are sexually active with a female of childbearing potential must agree to use effective methods of contraception and avoid sperm donation from Day 1 throughout the study and for 30 days after the final dose of study intervention. Exclusion Criteria: * Main portal, superior mesenteric vein, or splenic vein thrombosis with complete occlusion * Severe portal hypertension, as evidenced by gastrointestinal (GI) bleeding, thrombocytopenia with splenomegaly * Chronic pancreatitis * Active autoimmune disease or history of IgG4 related pancreatitis * Conversion to local resectability following prior treatment * Has received chemotherapy or an investigational agent within 14 days (or 5 half-lives, whichever is shorter) before screening * Has active, untreated brain metastasis * Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection * Has main portal vein thrombosis, or severe portal hypertension as defined by a history of variceal hemorrhage or active ascites accumulation refractory to medical management * Has Child-Pugh Class B or C cirrhosis. * Has experienced a Grade 3 or higher immune-related AE from prior CPI therapy * Is unable to be temporarily removed from chronic anticoagulation therapy * Has a history of bleeding disorder * Has active coronavirus disease 2019 (COVID-19), other severe infection, including a liver infection or acute pancreatitis, within 2 weeks before the first dose of study drug, or uncontrolled human immunodeficiency virus (HIV) infection at screening * Has had bacterial pneumonia within 8 weeks of first dose of study drug * Has active, known, or suspected autoimmune disease or immune-mediated disease. Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment or conditions not expected to recur in the absences of an external trigger are not exclusionary * Is receiving systemic steroid therapy \>10 mg of prednisone daily or equivalent or any other immunosuppressive medication at any dose level. Local steroid therapies (e.g., otic, ophthalmic, intra-articular or inhaled medications) are acceptable * Has significant concurrent or intercurrent illness, psychiatric disorder, or alcohol or chemical dependence that would, in the opinion of the Investigator and/or Medical Monitor, compromise their safety or compliance or interfere with interpretation of the study * Lactating women are excluded from study participation * Has previously received SD-101 * Medical history of significant hypersensitivity, severe and unresolved immune-mediated reactions, severe infusion-related reactions, or allergic reaction to TLR9 agonists or CPI agents in the judgment of the Investigator * Patients who were enrolled in the Phase 1 portion of the study will not be eligible for enrollment in Phase 1b