Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. The current project offers a promising solution that simultaneously kills tumor cells and change the tumor's microenvironment in favor of boosting our own body's defense system, i.e., the hosts' immune system.

Our group has found that a clinically used tumor ablation technique called irreversible electroporation (IRE) in combination with anti-PD-1 antibody, an immune checkpoint inhibitor, could cure about 40% of treated mice bearing an aggressive PDAC tumor in the pancreas. In order to find ways to further increase the rate of complete response, we analyzed tumor microenvironment and found that a type of immune...

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer. The current project offers a promising solution that simultaneously kills tumor cells and change the tumor's microenvironment in favor of boosting our own body's defense system, i.e., the hosts' immune system.

Our group has found that a clinically used tumor ablation technique called irreversible electroporation (IRE) in combination with anti-PD-1 antibody, an immune checkpoint inhibitor, could cure about 40% of treated mice bearing an aggressive PDAC tumor in the pancreas. In order to find ways to further increase the rate of complete response, we analyzed tumor microenvironment and found that a type of immune suppressive cells called myeloid-derived suppressor cells (MDSCs) are enriched at the tumor site. We further discovered that administration of a new drug formulation termed M-CPA/PTX that carries two drugs, cyclopamine (CPA) and paclitaxel (PTX), substantially changed the tumor microenvironment in favor of increasing the population of cytotoxic T lymphocytes, a type of immune cells required for the generation of antitumor immunity.

In this study, we will test the hypothesis that attenuation of the immunosuppressive tumor microenvironment by depletion of MDSCs or pharmacological modulation of tumor stroma by M-CPA/PTX potentiates combined therapy with IRE + anti-PD-1 to further prolong overall survival and increase the rate of durable response. We will first test the antitumor and anti-metastasis activity of the two rational combination strategies in clinically relevant mouse models of PDAC. We will then determine the impact of such treatments on recruitment and activation of cytotoxic T lymphocytes. If these new combination treatments are successful, this project will pave the way for clinical translation of potentially effective therapies for PDAC.

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