Intra-tumoral Mitazalimab (CD40 Antibody) With Irreversible Electroporation (IRE) in Locally Advanced Pancreas Cancer

Inclusion Criteria:

* Provision of signed and dated informed consent form
* Stated willingness to comply with all study procedures and availability for the duration of the study
* Histologically/cytologically-confirmed pancreatic ductal adenocarcinoma (PDAC)
* Persons, aged \> 18 years of age, as PDAC is extremely rare in pediatric populations.
* Locally advanced disease that is not amenable to surgical resection. Locally advanced PDAC cases will be identified per the definition developed by the Alliance for Clinical Trials in Oncology\[53\]. Per this definition, locally advanced PDAC is defined as presence of any one or more of the following on CT:

  * Occlusion of the superior mesenteric vein (SMV) and/or portal vein (PV) that is not amenable to resection and venous reconstruction
  * Interface between tumor and hepatic artery that is not amenable to resection and reconstruction
  * Interface between the tumor and superior mesenteric artery (SMA) measuring \> 180º of the circumference of the vessel wall
  * Interface between the tumor and celiac axis measuring \> 180º of the circumference of the vessel wall that is not amenable to resection
* ECOG Performance Status of 0-2
* Have adequate organ function per criteria below:

  * Absolute neutrophil count (ANC) ≥ 1.5x109/L
  * Platelets ≥ 100x109/L
  * Hemoglobin ≥9 g/dL
  * Serum creatinine ≤1.5 x ULN OR creatinine clearance ≥40 mL/min (as calculated by Modified Cockcroft-Gault formula)
  * Serum total bilirubin ≤ 1.5 X ULN
  * AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN
* A minimum of 4 months of one of the chemotherapy regimens preferred by the NCCN for good performance status patients (currently modified FOLFIRINOX, gemcitabine + albumin-bound paclitaxel, or NALIRIFOX)
* High quality imaging triphasic CT scan contrast-enhanced dynamic MRI of abdomen and either contrast-enhanced or non-contrast CT of chest and pelvis that demonstrate no evidence of metastatic disease within 30 days of enrollment
* FDG-PET imaging (skullbase-midthigh) at any timepoint between diagnosis and study intervention to determine whether tumor is PET-avid and evaluate for extra-pancreatic metastatic disease, as suggested by NCCN guidelines for high-risk patients.
* Tumor amenable to "in situ" (complete) ablation with maximum primary tumor dimension \< 4.0 cm
* For participants able to become pregnant: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method until the study intervention and for an additional 1 month after the study intervention.
* For participants able to cause a pregnancy: use of condoms or other methods to ensure effective contraception with partner for 1 month after study intervention.

Exclusion Criteria:

* Pregnancy or lactation
* Known allergic reactions to components of the mitazalimab solution (L-Histidine, trehalose, or polysorbate 20)
* Fever \> 38 degrees C within 14 days of study intervention
* Treatment with another investigational drug or other intervention within 30 days of enrollment
* Prior treatment with a CD40 antibody
* History of severe auto-immune disease
* The presence of metal fiducials or embolization coils within the tumor.
* Prior receipt of radiation therapy to the pancreas
* The presence of implanted metallic cardiac stimulation devices within the chest
* Uncontrolled cardiac arrhythmias that prevent synchronization of pulse delivery with the refractory period of the cardiac cycle
* Immunosuppressive doses of systemic medications, such as corticosteroids or absorbed topical corticosteroids (doses \> 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks (14 days) before study treatment administration. Physiologic doses of corticosteroids (≤ 10 mg/day of prednisone or its equivalent) or short pulses of corticosteroids (≤ 3 days) may be permitted.
* Any medical condition that precludes major abdominal surgery under general anesthesia
* Presence of distant metastatic disease (including positive peritoneal cytology) on staging laparoscopy and/or exploratory laparotomy at any timepoint.