Advanced pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths in the United States and can be attributed to deficiencies in early detection methods and effective therapies. Overexpression of indoleamine 2,3-dioxygenase (IDO) in PDAC plays a major role in accelerating disease progression by suppressing antitumor immunity. shIDO-ST is a novel Salmonella typhimirium (ST)-based therapy that expresses a small hairpin (sh) RNA to specifically silence tumor-derived IDO with decreased toxicity. ST as an shRNA delivery vehicle offers superior penetration against desmoplastic PDAC tissue and anti-metastatic function due to its motility and affinity for poorly vascularized, hypoxic tissue. Using bioluminescent forms of cell lines derived from pancreatic tumors, the Department of Experimental Therapeutics (ET) is able to employ advanced imaging techniques to follow therapeutic strategies in which Salmonella therapy is combined with proprietary adjuvant causing remarkable complete rejection of transplantable tumors (Project 5). To further understand the molecular mechanisms leading to PDAC tumor cell death, previous studies were conducted to best assess anti-PD1 mAb using genetically engineered orthotopic Kras and p53 mutant (KPC) PDAC mouse models that recapitulates desmoplasia and metastasis characteristic of human PDAC. Detailed mechanistic studies to understand how blockade of PD1 signaling networks induces PDAC regression were published in 2015. To improve penetration of tumors by shIDO-ST, PEGylated human recombinant hyaluronidase (PEGPH20, Halozyme Inc. by MTA) depletes hyaluronan abundant in PDAC tissue and increases vascular permeability. The combination of IDO silencing and abundant ST tumor colonization increases intra-tumoral concentrations of reactive oxygen species through the recruitment and activation of polymorphonuclear neutrophils (PMN), which can cause oxidative stress-induced apoptosis of tumor cells, cancer stem cells (CSC), and vascular stroma to inhibit PDAC progression. PMN are also known to have anti-metastatic function, thus providing additional protection against tumor spread. Project 5 evaluates the therapeutic effect of the combination therapy sh-IDO ST and PEGPH20 in pancreatic cancer models with human pancreatic cancer cell lines (Capan-2, HPAF-II, Hs766T) as well as a mouse transgenic pancreatic cancer cell line (KPC) carrying human IDO.
The p53 protein is a well-characterized suppressor of uncontrolled cell division. Mutations in the gene occur in > 50% of all patients with solid tumors, whereby it acquires oncogenic properties, and leads to high levels of dysfunctional p53 protein with malignant cells. The concentration of normal, non-mutant p53 in healthy cells is low, making p53 an attractive target for selective killing of tumor cells. To generate robust anti-p53 immune responses, a vaccine delivery platform was developed based on a highly attenuated virus referred to as Modified Vaccinia Ankara (MVA). Preclinical studies developed in our Department have shown that immunization of mice with p53-MVA vaccine causes rejection of established tumors and generation of systemic tumor immunity. In addition, when p53-MVA was used to generate cytotoxic T cells from the blood of cancer patients, these were capable of killing tumor cells in vitro. Recombinant MVA vaccinies have an impressive safety record, being administered in numerous clinical trials with only mild-side effects. In 2015, a first in human, Phase I clinical trial went to completion and evaluated the safety and immunogenicity of clinical grade p53MVA vaccine in patients with colon and pancreatic cancers was completed. Two ongoing clinical trials involve p53-MVA vaccination to test efficacy of the vaccine as a multimodal therapy in combination with two different immunomodulatory agents, gemcitabine or pembrolizumab (Project 3).