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Skip Viragh Center for Pancreatic Cancer

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Next Generation of Pancreatic Cancer Experts

The Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care attracts the most accomplished young investigators interested in pursuing a career in pancreatic cancer research and treatment. By training with established investigators, Skip Viragh Center fellows are helping advance the science and bringing much-needed new therapies to patients.

Hope For the Most Advanced Pancreatic Cancers

Katerine Beaver

Katherine Bever

Collaborating with Dung Le to bring hope to patients facing the worst form of pancreatic cancer. Bever and Le are developing clinical trials for patients with advanced pancreatic cancers that have spread outside of the pancreas. One immune therapy trial combines the pancreatic cancer vaccine GVAX to bring cancer-killing T cells to pancreatic tumors with immune checkpoint inhibitors to block PD-1 and IDO, that in many cancers act like an off-switch for T cells and shut down the immune response.

They plan to treat patients with PD-1 and IDO inhibitors and the GVAX vaccine followed by the listeria vaccine. Listeria bacteria augment the vaccine response and are engineered to express mesothelin, an immune cell-alerting antigen or tumor characteristic common to many pancreatic cancers. Bever hopes the combined approach will synergistically remove the breaks from the immune system and bring in T cells that will be specifically targeted to pancreatic cancer cells.

Immune therapy offers one of the only promising treatments for the most advanced pancreatic cancers that cannot be controlled with surgery, chemotherapy or radiation therapy.

Rare Findings Could Help Many

Rusty Johnson

Rusty Johnson

He would like to better understand rare immune cells involved in regulating the immune system’s response to cancer. These are cells that are so poorly understood that they have not been written about in most medical textbooks. Johnson believes a better understanding of these cells may lead to new, targeted treatments that could improve the effectiveness of existing immune therapies.

He was inspired by his earlier research of the IDO pathway, a mechanism tumors use to suppress the immune system and one that has been associated with poor outcomes in many types of cancer. IDO’s normal function is to help regulate the immune response and prevent immune cells from attacking normal cells, but cancer cells co-opt it to hide from the immune system. Clinical trials of drugs that block IDO appear to make other immune therapies work better.

Johnson believes there are many other cells and pathways that play a role in immune suppression. “Figuring out the mechanism behind how those cells work is critical to discovering new targets to stimulate antitumor immunity,” he says. Some, like IDO, may work through checkpoints to regulate the immune system, but others may have another primary mechanism of action. “What they do and how they do it is currently a black box,” says Johnson.

He is particularly interested in improving the activity of the pancreatic cancer vaccine developed and moved to the clinic by his mentors, Elizabeth Jaffee and Daniel Laheru. Vaccines accelerate the immune response, bringing in many powerful cancer-killing T cells, only to be held at bay by checkpoint inhibitors, like IDO, PD-1, CTLA-4, LAG3 and others, which put the brakes on the immune response. “I believe there are cells that can be both accelerators and brakes, depending upon their cellular environment. We need to harness that power and use it against cancer,” says Johnson. Targeting these cells with drugs in combination with other therapies would potentially improve anticancer immunity, he says.

He is confident that Kimmel Cancer Center immunology experts can decipher the complexity of the immune response. He argues that cancer isn’t as smart as it is often portrayed. It doesn’t intelligently select these regulatory processes to save itself; it just gets lucky, he says. He likens the cancer cell to a person working at a computer. “Rather than intelligently typing words into a computer, the cancer cell just presses a bunch of buttons on the keyboard until it finds one that works, and it keeps pushing it until it doesn’t work anymore,” says Johnson. “Cancer hasn’t outsmarted us. If it had, it would kill every time. It doesn’t. We get cures because we are smarter than the cancer. We just need to know what to target.”

Combining for a Cure

Valerie Lee

Valerie Lee

She is investigating a new treat­ment approach that may make currently incurable pancreatic cancers curable.

Working with Jaffee, Laheru, Lei Zheng and Ella-Mae Shupe, Lee’s focus is on locally advanced pancreatic cancer. Although the cancer has not invaded other organs (metastatic), it has begun to attach itself to the tissue and vessels around the pancreas and, as a result, it cannot be treated with surgery. About 40 percent of patients diagnosed have this form of the cancer. “Right now, we don’t have many treatment options for them,” says Lee. They receive the same treatment that patients with metastatic pancreatic cancer get, she says.

Lee’s approach could make curative surgery an option for many more patients. It combines anticancer drugs, a pancreatic cancer vaccine, an exciting new type of immune therapy known as an immune checkpoint blockade and a very precise form of radiation therapy called stereotactic body radiation therapy.

The therapy uses standard anticancer drugs to stabilize the cancer, followed by the Jaffee-developed pancreatic cancer vaccine. The vaccine awakens the immune system, summoning cancer-fighting killer T cells to the tumor. Treatment with a new checkpoint blockade immune therapy known as anti-PD-1 disrupts a mechanism cancer cells use to hide from these T cells. Lee hopes that together, these therapies will cause the patient’s own immune system to attack the cancer. Patients receive two doses of this combined regimen three weeks apart.

Next, patients begin five days of radiation therapy. This treatment destroys pancreatic cancer cells and also awakens the immune system, Lee says. As cancer cells die, they release their proteins into the body. Essentially, they show their true colors to the immune system, which now recognizes them as abnormal cells; immune cells are then deployed to the tumor. Patients will then, hopefully, get surgery and chemotherapy, followed by more immunotherapy, with the goal of keeping the tumors at bay.

With funding support from the United Company Charitable Foundation and the James W. and Frances Gibson McGlothlin Foundation of Bristol, Va, the Kimmel Cancer Center will soon begin a clinical trial in 54 patients to study the combined therapy. Lee wants to see if it works well enough against the cancer to get more patients to surgery, where their cancers could be cured. At a minimum, she hopes it will keep patients’ cancers from spreading- and potentially keep them in check for a long time.

No Pain, Significant Gain

Adrian Murphy

Adrian Murphy

Pancreatic cancers have a knack for hijacking the functions of cells around the tumor to create a cancer-friendly environment. Blocking these changes has been a focus for Zheng, an investigator in Jaffee’s laboratory.

Adrian Murphy has zeroed in on one of the changes identified by Zheng. Targeting it, he believes, could simultaneously fight the cancer and combat a common and painful side effect.

Zheng’s research revealed Sema3D as a neural highway of sorts, allowing cancer cells to hitchhike on nerve cells to travel away from the main tumor. This painful invasion of nerve cells is also deadly because it is a mechanism the cancer uses to spread—a mechanism, Murphy says, that is currently untargeted in pancreatic cancer therapy.

He hopes to change that and is working with Jaffee and Zheng to develop therapies that could block Sema3D. “If we develop drugs that inhibit this process, on the cancer,” says Murphy.

Pain is a common side effect for pancreatic cancer patients. Murphy says that many of the drugs used to treat nerve pain do not work well and have their own toxicities. What’s more, none of these therapies combat the root cause of the pain—the cancer. Murphy’s approach shows promise for accomplishing both by preventing the cancer from spreading to nerve cells.

He is currently scanning a library of FDA-approved drugs for potential Sema3D targets. Murphy will test drugs using a pancreatic cell line developed specifically to screen candidate drugs.

“Laboratory research shows that Sema3D is involved in pancreatic cancer metastasis,” says Murphy. “Using a drug to block it could benefit both the spread of cancer and the associated pain.”

Immune Therapy Combo and Nanomedicine

May Tun Saung

May Tun Saung

She is working with pancreatic cancer expert Lei Zheng to develop combination immunotherapies to improve the effectiveness of treatments. Saung is focusing on a particular type of immune cell called a macrophage. It is a large white blood cell that plays a critical role in the body’s immune response but is corrupted by cancer, switching roles to aid the tumor instead of destroying it. “Our goal is to convert macrophages from immune suppressing to immune activating,” says Saung.

In the laboratory, she is working with Zheng to explore drugs that target macrophages, in combination with GVAX and anti-PD-1 checkpoint inhibitors, to enhance the anti-tumor immune response.

She is developing a clinical trial that combines the pancreatic cancer vaccine, GVAX, anti-PD-1 immune checkpoint blockade and a macrophage-modulating agent in an effort to release the biological brakes the cancer cells places on the immune system.

Patients who have pancreatic cancers that currently cannot be successfully removed with surgery would first receive chemotherapy and radiation treatment followed by two rounds of treatment with immune therapy. Saung and Zheng hope the novel treatment approach will improve upon our current ability to knock back the tumor enough for surgical removal. Immune therapy continues after surgery to keep immune cells ignited against the cancer and to clean up any microscopic cancer cells that escape surgery.

Saung is forming collaborations with Justin Hanes, Director of the Center for Nanomedicine, and Hai-Quan Mao, Associate Director of the Institute for NanoBioTechnology, to develop nanoparticles that enhance tumor immunity. Nanoparticles are tiny nano-scale structures that are larger than molecules. In cancer medicine, they can be used to improve the effectiveness and efficiency of transporting drugs to tumors. Saung envisions nanoparticles loaded with tumor antigens to stir an immune response specifically against the cancer and immune therapy molecules on the surfaces to keep the immune response active. Precision medicine approaches are possible as patients’ tumors could be sequenced to identify the specific molecules that may provoke improved immune signals against the cancer cells. Nanoparticles could include these molecules to generate an anti-tumor response specific to a patient’s, unleashing a more potent immune response against the cancer.


Pancreatic Cancer and Beyond

Evanthia Roussos Torres

Evanthia RoussosTorres

Advances made in Jaffee’s laboratory have focused on pancreatic cancer, but what she and her team of investigators and clinicians have learned about immune therapy is being applied to other cancers.

This is the case for Evanthia Roussos Torres, who is working in the Jaffee lab with the hope of translating some of their immunology discoveries to breast cancer.

“Breast cancer traditionally is not thought of as highly immunogenic. The same is true of pancreatic cancer, so I thought investigating breast cancer the way we research pancreatic cancer might provide leads,” says Roussos Torres.

Using techniques fashioned in the Jaffee lab, Roussos Torres is exploring alterations in immune cells in and around the tumor that may be influencing the behavior of the cancer. “We want to teach the microenvironment in the tumor to be more immunogenic and help the cancer respond better to immune therapies,” she says.<</p>

Epigenetics is the study of alterations to the chemical environment of DNA that can change gene function. There is evidence that epigenetic-targeted drugs can prime the immune system to mount a better response against cancer. “We are hoping to use epigenetics to turn on gene expression that changes the types of immune cells that are able to enter the tumor and improve the response to immune therapy,” says Roussos Torres.

Her research has a basic science component aimed at studying the various immune therapies and their effects on the tumor and tumor microenvironment. From that, she hopes to develop a “readout of responses” that will provide clues about why certain immune therapies work or do not work. Understanding what occurs at the molecular level may reveal important biomarkers that can guide therapy.

On the clinical side, Jaffee and Roussos Torres are collaborating with their breast cancer colleagues Vered Stearns and Roisin Connolly, who are helping them collect tissue samples from patients receiving epigenetic therapy in conjunction with an immune therapy known as a PD-1 immune checkpoint inhibitor. “We know that there is potential for epigenetic therapies to make PD-1 immune therapy work better, but we don’t fully understand how or why it works. That’s what we’re hoping to uncover,” says Roussos Torres.

Initially, she will focus on triple-negative breast cancer because of the great need for more effective therapies, but she believes what they learn could possibly be applied to other types of breast cancer as well.

Using Pathology to Improve Immune Therapies

Liz Thompson

Liz Thompson

She is a new faculty member, collaborating with Skip Viragh Center co-directors Elizabeth Jaffee and Daniel Laheru, clinician-scientist Lei Zheng and pathologist Ralph Hruban. As a surgical pathologist, she is focused on deciphering and characterizing the immune response at all stages of pancreatic cancer, particularly how immune activity changes in response to different types of immune therapies. She expects this research to reveal new immune targets for therapy and biomarkers that predict whether a cancer will or will not respond to immune therapy.

Thompson will compare tumor biopsies obtained before treatment to samples taken at surgery. For pancreatic cancers that cannot be treated with surgery, she will use biopsies taken at different time points throughout diagnosis and treatment. Thompson will use advanced technologies, such as flow cytometry and DNA sequencing, to sort through and collect immune cells for study and to identify proteins that influence immune activity. In addition, a sophisticated technology known as multiplex immunohistochemistry will be used to visualize the spatial composition of immune cells within tumors.

“Cancers tend to change, mutating their DNA to survive in the face of different treatments,” says Thompson. “This work will help us better understand and target these changes to keep the immune system active as the tumor evolves.”

Her ultimate goal is to convert even the most advanced pancreatic cancers to a chronic, manageable disease.

Combinations That Make Vaccine Therapy Work Better

Mark Yarchoan

Mark Yarchoan

Mark Yarchoan, the Linda Rubin Fellow, is hoping to build upon Jaffee’s work on the pancreatic cancer vaccine. He is studying whether combining additional immune therapies with the vaccine makes the killer T cells the vaccine recruits to tumors better at destroying cancer cells.

Before Jaffee and team’s pancreatic cancer vaccine, cancer-fighting immune cells were not usually found in pancreatic tumors, says Yarchoan. “I’m hoping we can push immune therapy even further by adding in additional immunotherapies that make T cells work better within the cancer,” he says.

“In melanoma, patients are more likely to respond to a combination of ipilumumab and nivolumab than if either agent is used alone,” says Yarchoan. The drugs are known as a checkpoint inhibitors for their ability to shut down a mechanism that cancer cells use to suppress an immune response. Ipilimumab targets the CTLA-4 immune checkpoint, and nivolumab targets the PD-1 checkpoint, but there are many others checkpoints that have been identified, including IDO, LAG3 and CD40, that can be targeted with other inhibitors. Yarchoan believes adding a checkpoint inhibitor to vaccine therapy might improve responses in pancreatic cancer as adding ipilumumab to nivolumab did in melanoma.

PD-1 checkpoint inhibitor therapy has been a major breakthrough at the Kimmel Cancer Center, resulting in remarkable responses in melanoma and lung cancer, and showing the potential to have benefit across essentially all cancer types. “The research is so new that no one knows what to mix the PD-1 inhibitors with at this point for pancreatic cancer,” says Yarchoan. “I want to learn how we can add in other immune checkpoint inhibitors to take advantage of the incredible T cell activation the vaccine gives us.” The first step of his research will focus on defining the best checkpoint inhibitors—or combinations of inhibitors—to add with the vaccine.

“The vaccine is the first step in turning pancreatic cancer into an immune-responsive cancer. Now that the vaccine has gotten T cells into the cancer, we need to let them do their work by removing as many blocks against the immune system as we can,” says Yarchoan.

Although still in a very early stage, he is also investigating opportunities to apply precision, or personalized, medicine to immune therapy. Yarchoan will explore whether the mechanism that prevents T cells from doing their job may vary among patients. “Potentially, we could customize what we combine the vaccine with at an individual level,” he says. His ultimate goal is to broaden and improve response rates to the pancreatic cancer vaccine.