Posted December 20, 2017

Michael Curran, Ph.D., The University of Texas MD Anderson Cancer Center

Pancreatic cancer accounts for 7% of all cancer deaths in the United States.¹ Considered one of the deadliest cancers, pancreatic cancer excels at hiding from the immune system by surrounding itself with an immunosuppressive barrier. As a result, immunotherapeutic approaches, such as the use of T cell immune checkpoint blockades, have failed to impact patient survival. The inability of therapeutics to penetrate the protective barrier and kill the sequestered cancer cells is a critical gap in pancreatic cancer research and therapy. In Fiscal Year 2014 the Peer Reviewed Cancer Research Program funded the work of Dr. Michael Curran through a Career Development Award to address this gap. Dr. Curran is one of the first to describe a combination of immunotherapies recently fast-tracked by the U.S. Food and Drug Administration for treatment of patients with metastatic melanoma. Dr. Curran aimed to use his immunotherapy experience and, with the help of his mentor, Dr. Stephen E. Ullrich, establish himself within the pancreatic cancer research community.

Dr. Curran's preliminary work examined how the immune system was suppressed by the tumor and the surrounding myeloid stroma, or tissues in pancreatic ductal adenocarcinoma. Dr. Curran hypothesized that it was possible to take advantage of the stroma by using immune cell agonists to help, rather than hinder, the immune system. Dr. Curran proposed a combination of T cell stimulation with a Stimulator of Interferon Genes (STING) agonist. A STING agonist would activate a strong type I interferon response, leading to immune cells reaction. The STING pathway has been shown to contribute to the stimulation of specific anti-cancer immune responses in other forms of cancer, such as acute myeloid leukemia.² Dr. Curran believed that STING agonists would trigger the stroma surrounding a tumor to produce a pro-inflammatory environment, thus leaving the tumor vulnerable to immunotherapeutics as the suppressive characteristic of the stromal barrier would be negated.

However, another major research gap in the pancreatic cancer field significantly slowed Dr. Curran's progress: the unavailability of a mouse model of pancreatic cancer that mimicked human disease. Through his exhaustive efforts, Dr. Curran discovered that a transplantable pancreatic cancer cell line created by his collaborator Dr. Tuveson was, like it's human counterpart, almost completely resistant to T cell checkpoint blockade using CTLA-4/PD-1 inhibitors. These tumor cells could be surgically implanted in mice to generate a �pseudo-metastatic� model of pancreatic cancer. Dr. Curran's efforts resulted in an improved animal model that more closely represents human pancreatic cancer. Dr. Curran's model may be used by the research community at large to advance pancreatic cancer diagnosis and treatment.

In addition to the lack of a feasible animal model, Dr. Curran also noted the lack of efficient assays capable of comparing agonist and immunotherapeutic combinations would also slow progress. In order to identify the optimal STING-centered combination therapy, Dr. Curran recognized the need to characterize how different STING agonists trigger the myeloid-derived cells to change from a suppressive to a pro-immune, or pro-inflammatory, state. While there were protocols available that could be used to characterize the agonists, there was not an efficient tool capable of identifying which agonist combinations were the most effective. After recognizing the need for an improved toolset to expedite pancreatic research, Dr. Curran's work, in part, focused on the development of such an assay. By using suppressive cells derived from intact MT4 pancreatic tumors, Dr. Curran was able to characterize the mechanisms of suppression and develop a novel assay capable of identifying which agonist combinations were optimal.

Having established that STING agonists could trigger the stroma surrounding a pancreatic tumor to produce a pro-inflammatory environment, Dr. Curran's work has progressed toward the final stage: testing combination T cell checkpoint blockade and STING agonists in the newly developed �pseudo-metastatic� model. In addition, Dr. Curran's tool kit of a new murine model of pancreatic cancer and an assay will expedite his work aimed at reprogramming the immunosuppressive myeloid stroma surrounding pancreatic tumors to support pancreatic cancer therapy. Dr. Curran's mouse model of pancreatic cancer could open the door for the development of a truly impactful therapy that will improve survival rates.

Links:

Public and Technical Abstracts: Immunologic Rejection of Pancreatic Cancer Without Autoimmune Side Effects

¹ https://www.cancer.org/cancer/pancreatic-cancer/about.html

² http://www.cell.com/cell-reports/pdf/S2211-1247(16)30591-5.pdf

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