UNIVERSITY OF MINNESOTA FOUNDATION
April 5, 2017

Try, try again

When a homegrown cancer therapy didn’t work as anticipated, U researchers went back to the lab to find—and solve—the problem

Hope was high as University of Minnesota scientists and physicians tested a therapy designed to fight off deadly brain tumors during a 2012 clinical trial. In most cases, the immunotherapy—which was developed at the U and trains a person’s own immune system to fight off disease—performed admirably to prolong adults’ and children’s lives by preventing their tumors from returning. But the progress was short-lived when the tumors eventually came roaring back.

The team’s curiosity about what went wrong led to an important discovery of a little-known protein called CD200. Turns out it plays a leading role in suppressing the immune system and perpetuating brain cancer. Such findings by researchers Christopher Moertel, M.D., and Michael Olin, Ph.D., hold the potential to make the next big breakthrough in brain cancer treatment. 

The clinical–scientific pair aims to launch a human clinical study later this year that would test a new cancer immunotherapy based on their CD200 discoveries. They are building on the successes they’ve had treating dogs that have similar naturally occurring brain tumors, prolonging their lives from typically just weeks after diagnosis to more than a year and a half.

Christopher Moertel in a chemo infusion room
Pediatric neuro-oncologist Christopher Moertel, M.D., says philanthropy has helped his team advance from baby steps to big leaps in their work. (Photo courtesy of University of Minnesota Health)

“I think we can probably show a similar difference in humans,” says Moertel, a pediatric neuro-oncologist at University of Minnesota Masonic Children’s Hospital and holder of the Kenneth and Betty Jayne Dahlberg Endowed Professorship in Pediatric Brain Tumor Research.

Learning from failure

Brain tumors are often aggressive, wily, and difficult or impossible to treat. Brain cancer is the second-most common form of cancer in children and the leading cause of cancer-related deaths in children.

Masonic Cancer Center members Olin and Moertel are driven to make a difference in treating this devastating disease. Olin’s mother died from it, and Moertel has watched countless children struggle—and fail—to beat it.

After the unsuccessful brain tumor clinical trial in 2012, Olin went on a quest to find out why this therapy, which seemed to have so much potential, didn’t work. He found himself comparing blood samples that were taken weekly from study participants. A neuro-immunologist and assistant professor of pediatric hematology/oncology, Olin focused on changes in proteins in the blood, evaluating an alphabetical list of proteins one by one when he noticed slight changes in CD200 levels.

Patients who didn’t respond to the immunotherapy at all had sky-high CD200 levels. Those who responded well to the therapy had low CD200 levels initially but high levels when the tumors returned.

“It was our theory that CD200 was important and the reason the tumors returned,” Moertel says. “It turns out that CD200 is an important immunosuppressant agent that tumors make to escape discovery by the immune system.”

Though there had been some scientific interest in CD200’s abilities to shut down the immune system, research in this area hadn’t made much progress. When the U of M team began doing experiments, Olin found that blocking CD200 in mice made their brain tumors disappear. Blocking CD200 also killed human tumor cells in a petri dish.

Finding this promising, Olin began analyzing CD200 more closely and got even better news. Not only does blocking CD200 keep tumors at bay, it also has the ability to transform from bad cop to good cop. Olin found that chains of amino acids called peptides turn on the protein’s unique activation receptors, which then overpower the CD200 protein, transforming it from perpetuating cancer to fighting it.

Moertel and Olin partnered with Liz Pluhar, D.V.M., Ph.D., a professor of veterinary clinical services at the University, to evaluate their CD200 theory on dogs that develop brain tumors. Canine and human brain tumors are very similar, as are the canine and human immune systems. The partnership has both improved care for dogs that have brain tumors and served as a productive trial run for the human version of the therapy.

In fact, using a new form of the therapy with a CD200 blocker has extended some dogs’ lives to more than 500 days, when typically their brain tumors would have killed them in weeks.

“We’ve seen some fantastic results,” Olin says.

Back to the clinic

The team now is working to bring these discoveries to humans via a series of new clinical studies. Getting there will still take significant effort, including toxicity testing, approval from the U.S. Food and Drug Administration, and funding.

The work has benefited greatly from federal research grants and philanthropic support, such as that from the Dahlberg Family Foundation and significant donations from Bob and Corinne Ferris, Children’s Cancer Research Fund (CCRF), CCRF’s Dr. Daniel G. Carey Brain Tumor Research Fund, the American Brain Tumor Association, Randy Shaver Cancer Research and Community Fund, Humor to Fight the Tumor, and Love Your Melon.

“We have a long list of people who have made a significant contribution to this work and helped us move the research along,” says Moertel, who has worked in pediatric oncology for nearly 30 years. “Before we were taking baby steps. This work is a big leap.”

Because this research is inherently expensive, Moertel and Olin spun out a company from the University called OX2 Therapeutics to create an avenue for venture capital investments. They see the promise of their work in fighting brain cancer and want to help patients as quickly as possible while also expanding the anti-CD200 immunotherapy model to other cancers.

“This will be a rock star for breast cancer and melanoma as well,” Olin says. “If we give the inhibitor to mice modeling human breast cancer, they have an 80 percent survival rate.”

It’s part of the team’s shared vision and lifelong goal of stopping cancer in its tracks.

“We want to cure brain tumors. That’s why I do my job,” Moertel says. “When I look at kids every single day who don’t have a cure for their disease, it’s heartbreaking. I want to find an answer.”

With $1 million raised so far, the team is close to being ready to launch the first Phase I clinical trial. For more information about this research or how to support it, contact Jen Foss at 612-626-5276 or foss@umn.edu.

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