ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is the 3rd most deadly cancers with a 5-year survival rate of only 3% in patients with metastases. Current efforts to improve outcomes in PDA have yet to significantly extend patient survival. This is in part due to the fact that 80-90% of PDA cases are not surgically resectable and exhibit local or distant metastases upon diagnosis, thereby significantly shortening survival. The most aggressive and toxic chemotherapy cocktail regimen, FOLFIRINOX, fails to extend median survival beyond 11.1 months. While combinations of chemotherapy with immunotherapy (chemo-immunotherapy) have been paradigm-shifting for several primary and metastatic cancers, they still fail to significantly extend PDA patient survival. For example, chemo-immunotherapy using gemcitabine, nab-Paclitaxel and Pembrolizumab extended overall survival in PDA patients to only 15 months. As such, there remains a critical need for transformative modalities that improve response rates to chemo-immunotherapy in PDA patients. Chemo-immunotherapy is largely limited in PDA by desmoplasia which contributes to 1) poor drug delivery, and 2) an immunosuppressive tumor microenvironment that neutralizes the action of immunotherapies. This project capitalizes on a non-toxic light- activated modality known as photodynamic priming (PDP), which we have shown to directly remediate desmoplasia. In doing so, PDP augments the delivery of small molecular weight therapeutics, monoclonal antibodies, and nanomedicines, and also mechanistically sensitize tumors to both chemotherapy and immunotherapy. Furthermore, we and others have shown that PDP induces T cell mediated anti-tumor responses, thereby synergizing with immune-checkpoint blockade. In this proposal, we will use optical molecular imaging to direct the engineering of a single PD-L1 targeted liposome that delivers PDP and chemo-immunotherapy in a spatiotemporal, synchronized fashion. We will use syngeneic models representing T cell inflamed and non-T cell inflamed PDA tumors, Genetically Engineered Mouse Models, and orthotopic patient-derived PDA xenograft models in order to: 1) promote a homogenous tumor deposition of chemotherapy and immunotherapy agents, 2) mechanistically sensitize tumors to chemotherapy, 3) induce immunogenic cell death, and 4) provoke a T cell mediated anti-tumor attack. By first remediating desmoplasia, we propose that a single targeted liposome integrating PDP and chemo-immunotherapy will improve PDA responsiveness at considerably lower chemotherapy doses, thereby prolonging patient survival, while mitigating dose-limiting toxicities and improving patient quality of life.

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma is the 3rd deadliest cancer in the US with only 3% of patients surviving beyond 5 years after the cancer has spread. Less than 25% of patients are eligible for surgery, and the effects of chemotherapy and immunotherapy are limited by various barriers in the tumor immediate environment. This project harnesses a light-activated priming treatment to restore the effects of chemotherapy, improve the immune system’s ability to eliminate the tumor, and prolong survival rates.