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.
