Up to 40% of patients with pancreatic cancer present with locally advanced pancreas cancer (LAPC), defined as localized (non-metastatic) but unresectable. Treatment of this patient subset is a particularly glaring unmet need. Irreversible electroporation (IRE) is a technique that is being used increasingly for ablation of persistent LAPC after systemic therapy. Our group has demonstrated that IRE can function as an "in situ vaccine" by releasing tumor neoantigens in the setting of inflammation and thereby promoting recognition of the tumor by the innate immune system. CD40 is an immune receptor located on antigen-presenting cells that serves as a bridge between the innate immune system and the host’s specific response to neoantigens (the adaptive immune system). Using immunocompetent orthotopic mouse models of pancreatic cancer, we have shown that the combination of IRE with local delivery of a CD40 agonistic antibody (CD40 Ab), can both improve the local effects of IRE and decrease metastatic disease in the liver. ADC-1013 (mitazalimab) is a CD40 antibody that is currently being studied in clinical trials as a systemic therapy for metastatic pancreatic cancer. It has also been delivered by local (intratumoral) injection into a variety of superficial and deep tumors. Local (intratumoral) delivery is appealing in that it has potential to be more effective while decreasing systemic side effects. Intratumoral injection is also feasible at the time of IRE, which is generally performed via an open surgical approach. We hypothesize that local delivery of a CD40 agonist at the time of IRE in patients with LAPC will augment the systemic immune effects of IRE, enhance local disease control, and ultimately decrease distant recurrence. We propose to conduct a phase I study of intratumoral mitazalimab injection at the time of surgical IRE to determine a recommended Phase 2 dose and establish preliminary efficacy for future studies. In parallel, we will perform correlative studies to determine if this combination can generate immune responses to neoantigens identified using an unbiased bioinformatic analysis pipeline of tumor biopsies. Our multi-disciplinary team is uniquely qualified to conduct the proposed studies. Dr. White is a surgical oncologist at UCSD with clinical expertise in IRE and whose laboratory generated the preliminary data. Dr. Wainberg is a medical oncologist at UCLA with expertise in immuno-oncology clinical trials and specifically CD40 agonists. Subjects will be recruited from all five of the University of California Pancreatic Cancer Consortium centers. Dr. Schoenberger, at the La Jolla Institute for Immunology, will assist with neoantigen identification from human tumor samples and measurement of immune responses in post-treatment blood samples. We hypothesize that this novel approach to the treatment of LAPC will prove to be safe, and result in progression-free survival superior to that of patients previously treated with IRE alone. Wi...