Engineered Living Materials as Programmable Therapeutic Implants for Pancreatic Cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) represents 95% of all pancreatic cancers and has a five-year survival rate below 13%. Even after surgical resection, the only curative option available to approximately 20% of patients, recurrence exceeds 80%. Current treatment strategies, including systemic chemotherapy and immunotherapy, are limited by poor drug delivery to the tumor site, off-target toxicity, and an inability to coordinate the multiple therapeutic signals needed to overcome PDAC immunosuppression. Existing implantable drug depots offer a promising local delivery strategy but are constrained by finite drug loading and burst release kinetics, lacking the capacity for dynamic, temporally controlled delivery that is critical to overcome the profound immunosuppression and dense desmoplastic stroma of the PDAC tumor microenvironment. During the K99 phase of this award, I developed an implantable living material (ILM) platform that encapsulates engineered bacteria within mechanically robust hydrogels, demonstrating bacterial containment and functional genetic circuit activity in vivo. The proposed research leverages this platform to deliver sequential immunotherapies designed to first kill tumor cells and remodel the surrounding stroma, then recruit and activate the immune system to mount a durable antitumoral response. To achieve precise temporal control over this therapeutic sequence, I will engineer genetic circuits that coordinate synchronized drug releases from uniform bacterial compartments within ILMs, enabling programmable switching between delivery phases. The sequential delivery system will be engineered and characterized in vitro, evaluated for therapeutic efficacy and immune responses in syngeneic PDAC models, and validated in a genetically engineered mouse model that recapitulates the clinical features of human PDAC, including comparison with standard chemotherapy. Immunocompetent animal models are essential because the interplay between engineered bacteria, sequential drug delivery, and the intact tumor immune microenvironment cannot be recapitulated in vitro. This interdisciplinary research, combining biomaterials engineering, synthetic biology, and cancer immunology, directly aligns with the mission of the National Cancer Institute to advance the understanding and treatment of cancer. By addressing the specific delivery and immunosuppressive barriers that have limited immunotherapy in PDAC, this project has the potential to establish a programmable immunotherapy platform that is generalizable to other solid tumors requiring localized therapeutic intervention.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE A long-standing challenge of pancreatic cancer is poor drug delivery and immunosuppressive environment, con- tributing to reduced drug efficacy and a low survival rate. Implantable drug depots enable direct therapeutic targeting of tumors but often lack the precise dosage and kinetics control necessary for effective treatment. This proposal integrates genetically engineered bacteria within implantable materials, creating novel engineered living materials that locally and dynamically deliver anticancer therapeutics to orchestrate cytotoxic effects and anti- tumoral immunity against pancreatic cancer.