Project 2: Intratumoral PDT Induces PDP-based Enhancement of PD-1 Inhibition in Pancreatic Carcinoma

ABSTRACT - Project 2 Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and typically presents at advanced stages. Progress in treating these cancers has been slow and has produced only very modest increases in survival. One of the few positive developments has been the use of immune checkpoint inhibitors (ICI) in the setting of PDAC with microsatellite instability (MSI). Unfortunately, MSI is uncommonly found in these cancers. The goal of this project is to expand the usage of ICI to the majority of PDAC tumors by stimulating the immune system via photodynamic priming (PDP) of the primary tumor, using the intravenous photosensitizer Verteporfin which is activated by light delivered via an optical fiber delivered though a fine needle into the tumor under endoscopic ultrasound or CT guidance. This initiates PDP, a process that activates immune cell recruitment into the tumor and educates T-cells to mount a response against the primary PDAC as well as peripheral metastasis. We had a patient in whom a pulmonary metastasis regressed after PDP treatment of the primary cancer, without any additional chemotherapy or immunotherapy. In addition, we were able to show an increase in tumor-directed T cells (responsive to ICI) in the peripheral blood of another patient 72 hours after we administered PDP for pancreatic cancer. In Project 2, we will perform a Phase II study using combination therapy with PDP (Veteporfin and red light) followed by ICI (pembrolizumab). Aim 1 will assess this combination treatment in 25 patients with locally advanced or advanced pancreatic cancer (oligometastasis), for its ability to increase overall and disease specific survival, produce necrosis of the primary tumor and regression of metastatic disease; we will also monitor for any toxicities. Dosimetry for PDP will be based on vascular perfusion of the tumor on CT scans as well as fluorescence measurements from the buccal mucosa (with Core C), avoiding direct measurements in the tumor which were found to be unreliable previously. Aim 2 will use a PDP radiometric index (found in residual tumor after PDP) to predict response to ICI. The index is based on changes in tumor characteristics related to the degree of inflammatory infiltrate that is reflected in tumor heterogenity. We will also use hyperspectral fluorescence microendoscopy to evaluate lymphocytes from lymph nodes with metastatic disease involvement (Core B), to determine if this correlates with the subpopulations found by flow cytometry. Finally, Aim 3 will focus on PDP-stimulated immune cell changes in peripheral blood lymphocytes of our PDAC patients, to determine if these changes correlate with post-PDP changes in lymphocyte sub-populations observed after PDP in skin tumors (Project 1) that are known to be immune sensitive (squamous cell cancer) and those that are not (basal cell cancer). Finally, in a group of 5 patients we will be sampling large metastatic lymph nodes 3 days after PDP to assess the changes in immune cells, in order to determine whether ICI responsive tumor directed T-cells will increase.