February 6, 2020

Improving outcomes for brain cancer

Mahua Dey portrait

Madison, Wis. — While overall outcomes for individuals with cancer are steadily improving, new treatments like immunotherapy have had limited success in malignant brain tumors.

New UW Carbone Cancer Center member, Mahua Dey, MD, an assistant professor in the Department of Neurological Surgery and director of surgical neuro-oncology program at the UW School of Medicine and Public Health, studies the immune system’s response in glioblastoma (GBM) and how that response could be manipulated in the clinic through immunotherapy to get rid of these brain tumors. Dey came to UW-Madison’s campus excited about the vision held by Robert Dempsey, MD, to build a brain tumor program that incorporates excellent basic science research into outstanding clinical care.

“You need those two combined to really form a translational brain tumor program where we can offer new and unique treatment strategies for brain tumor patients here in Wisconsin,” Dey said. “Standard of care is just the beginning: our goal is to go beyond that and bring an innovative multimodal treatment strategy for patients suffering from this deadly disease.”

Her research focuses on two specialized cells that regulate the immune system response: dendritic cells and T cells. Our bodies come into contact with toxins or other foreign substances every day, and the ultimate immune response to any antigen is the result of a complex interplay between dendritic cells and T cells. The dendritic cells are responsible for recognizing antigens and presenting them to T cells. Depending on the context, the antigens presented to the dendritic cells either activate T cells to mount an immune response or inactivate T cells to avoid auto-immunity.

“It’s like if you're driving a car, you have to both take your foot off the brake and you have to push on the gas, otherwise that car doesn't move,” Dey said. “With the immune system, you have to take off the inhibition, or these checkpoint inhibitors, but then you also have to press on the gas, which is teaching these dendritic cells to teach the T cells that there's a foreign antigen they should react to.”

But retraining the dendritic cells to recognize the tiny differences between tumor cells and healthy cells can be tricky. Dendritic cells grown in artificial conditions in a lab are also not as good at inducing an immune response as those that grow in the body. Now, Dey’s research has shown that in mouse models, exposing natural dendritic cells to a tumor antigen overnight and then injecting back induces a bigger response than those cultured in the lab.

Rather than go directly from this data in mice to human clinical trials, Dey is collaborating with a colleague in veterinary medicine at Purdue University who treats brain tumors in dogs.

“We know a lot more about GBM now than we did say 20 years ago, but where mouse models have failed is to show the efficacy of immunotherapy,” Dey said.

They have recently shown that dogs develop brain cancers that are similar to humans, meaning our furry companions may be able to help us find new therapies.

Dey is also interested in understanding metastatic brain tumors at the molecular and genomic level to better design clinical trials. She is the principal investigator of an innovative phase II clinical trial studying upfront radiosurgery prior to surgical resection in people with cancers that have moved from the primary cancer site into their brains. While the standard of care is to surgically remove the tumor and then radiate that region, high recurrence rates suggest that the timing and dosage of the radiation might not be effective.

“Our trial is unique in the sense that we have that biological component to explain both our success or failure,” Dey said. “I think every trial is an opportunity to learn, and even if it didn't work, we should figure out why didn't it work.”

By analyzing the molecular profiles of the tumor cells, Dey says they will be able to determine how the radiation is affecting them.

“Until we have a good understanding of the basic biology of these tumors and how they behave, we're not going to be really designing a clinical trial that actually makes a difference,” she said.