Engineering a hydrogel-based vaccine to prevent recurrence in pancreatic ductal adenocarcinoma

Purpose: Surgical resection remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC), yet only 15% of patients are resectable at diagnosis and up to 40% of patients present with locally advanced tumors involving vital vasculature. Even among those who undergo resection, recurrence rates exceed 60%. To address this, we conceived the idea of a locally implantable hydrogel (PancVax) capable of sustained release of an adjuvant therapeutic over a week post-operative to induce a sustained immune response in a murine model pancreatic cancer involving incomplete resection. Materials and Methods: We engineered a mechanically tough interpenetrating network consisting of carboxyethyl chitosan with dynamic covalent crosslinks and ionically crosslinked alginate. Hydrogel biocompatibility was assessed incubating hydrogel components with RAW264.7 macrophage cell line and assessing markers for apoptosis and maturation. Release assays were conducted by assessment of the hydrogel supernatant following incubation. Compression failure testing was performed to assess the compression toughness. Our murine model for incomplete resection of pancreatic cancer involved orthotopically implanting a KPC-embedded collagen hydrogel at D0 and performing an incomplete tumor resection and implantation of PancVax at D12. Treatment response to adjuvant therapeutics embedded in the PancVax was monitored through tumor volume, collagen staining, and immune profiling. Results: Individual hydrogel components were incubated for 24 hours with RAW264.7 macrophages, demonstrating >97% cell viability and <1% MHC-II+ demonstrating cytocompatibility and minimal macrophage activation. The hydrogel released albumin-FITC as a model of cytokines and peptides over a week with a sustained release profile. Hydrogels were microporous, showed a compression toughness of 60.8 kJ/m 3 , and maintained structural integrity during suture fixation. Implantation of PancVax with encapsulated adjuvants after tumor resection resulted in a significant reduction in tumor volume compared to resection alone (p<0.01). Conclusion: We successfully developed a hydrogel-based vaccine vehicle with properties of sustained release, high mechanical toughness suitable for suture fixation, and sufficient microporous structure permissive for cell trafficking. This work presents a novel perioperative hydrogel-based immunotherapy platform with the potential to shift the treatment paradigm for PDAC by improving post-surgical tumor control and expanding the pool of patients eligible for curative-intent surgery.