Interstitial Chemophototherapy as an Intervention in Locally Advanced Pancreatic Cancer

Long-circulating liposomal irinotecan is approved for metastatic pancreatic cancer (PaCa). We developed a modified formulation that stably integrates porphyrin-phospholipid (PoP) into the bilayer of liposomes without exchanging with serum factors when circulating in blood. This provides for light-triggered drug delivery to irradiated tumors, enhancing IRT delivery by an order of magnitude and inducing potent tumor regression in multiple PaCa murine models. Our goal is to translate this concept into interstitial chemophototherapy (I-CPT) as a tumor ablation paradigm for locally advanced PaCa. I-CPT involves image-guided placement of multiple diffusing optical fibers into large tumors. I-CPT will be a clinically relevant approach for PaCa, as opposed to external beam CPT which has been the basis of our studies so far. This R01 addressing PAR-22-071 Toward Translation of Nanotechnology Cancer Interventions (TTNCI) will advance long-circulating IRT PoP liposomes (IRT-PoP) for photoablation of large PaCa tumors models in using clinically relevant treatment and dosimetry regimes, in combination with immune checkpoint blockade (ICB) and advanced PaCa tumor models for assessing biodistribution and pharmacokinetics. Pancreatic cancer (PaCa) has amongst the poorest prognosis of any cancer type, with a 5-year survival rate of ~10%. Poor tumor perfusion contributes to the failure of conventional therapies due in large part to stromal amplification and hypovascularity that comprise a delivery barrier that limits drug deposition. This hypovascular environment also limits efficacy of other ablative techniques that require molecular oxygen, such as radiation therapy and photodynamic therapy. We demonstrated that CPT dramatically overcomes poor drug delivery to PaCa tumor models, typically delivering an order of magnitude more drug, based on mechanisms including vascular permeabilization and drug release from the carrier. IRT-PoP CPT co-treatment with PD-1 improved delivery to PaCa tumors leading to durable cures in mice. In Aim 1 we will define I-CPT light dosimetry in locally advanced PaCa in preclinical models, this includes a patient-derived xenograft model developed at Roswell Park that mimics the histological and hypovascular features of PaCa, and an orthotopic pancreatic tumor model to allow large tumors to be treated. In Aim 2 we will characterize IRT-PoP drug release and enhanced immunotherapy effects in an orthotopic KPC mouse model. In Aim 3 we will use large PDX tumors in a nude rat model to model the pharmacokinetics and pharmacodynamics of I-CPT.