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Under the Microscope: Enlisting the Body’s Own Defenses in the War on Cancer

Immunotherapies, which use a patient’s immune system to fight cancer, show promise for treating several pediatric cancers. With V Foundation funding, two research groups are exploring innovative approaches to seek and destroy cancer cells within the body.

Tricking the immune system with a tweaked polio virus

Many times in his career David Ashley, MD, PhD, has diagnosed children with aggressive brain tumors known as diffuse pontine glioma and delivered the grim diagnosis to families. That part of his work never gets easier.

“It’s basically a death sentence,” he says of the inoperable tumors that form in the brain stem and grow among nerves and healthy cells. “There are no effective treatments.”

With funding from the V Foundation, Ashley, Director of Duke University’s Preston Robert Tisch Brain Tumor Center, and his colleagues plan to change the prognosis for children with diffuse pontine gliomas. Ashley applies immunotherapy, along with growing knowledge about the genetic causes of brain tumors, to develop treatments that could mean longer lives for these children, most of whom die within a year of diagnosis.

Ashley and his colleagues at Duke target brain tumors using a modified, nonpathogenic form of the polio virus called PVSRIPO. The researchers engineer the virus so that it can detect mutations in the gene H3F3A, which are often associated with brain tumors. When the modified virus is injected directly into a patient’s tumor, the virus is able to detect and invade cancerous cells. In turn, the presence of the polio virus stimulates an immune response, causing the body’s own immune cells to attack and kill the cancer cells.

“The challenge with immunotherapy is to stimulate a response that is targeted, but strong enough to affect the tumor,” says Ashley. “Viruses are useful because our immune systems are designed to respond to a viral infection. The virus can recognize the cancer cells and it tricks the immune system into responding.”

Experimental therapy using the polio virus has been tried on 100 adults at the Duke Brain Tumor Center with aggressive brain tumors. Preliminary results show the treatments often shrink tumors and can extend the lives of patients.

The V Foundation funding, provided with support from the Buster and Kristen Posey Fund and the Apple Gold Group, will extend these experimental treatments to children and provide the evidence needed for the Food and Drug Administration to approve clinical trials. The researchers currently inject the polio virus directly into tumors, but they plan to modify the virus so it can be administered through a shot, like a vaccine.

“We want to show that this is a viable approach to a type of cancer that is now 100 percent fatal,” says Ashley. “If so, the same approach could be translated into treatments for other kinds of solid tumors.”

Helping more kids benefit from CAR-T therapy

Immunotherapy has already improved the odds for children with acute lymphoblastic leukemia (ALL). In a treatment known as CAR-T therapy, doctors engineer a patient’s T cells (a type of immune system cell) by adding a chimeric antigen receptor (CAR) that can bind to a specific protein found on cancer cells. Once unleashed in the body, the engineered T cells seek out and destroy the cancer cells.

CAR-T therapy has transformed treatment for B-cell malignancies, which includes ALL, in both children and adults. However, in children receiving CAR -T therapy for B-cell acute leukemia, about a third of patients suffer relapses and no longer express the targeted protein. When the cancer cells express different forms of the targeted protein, they can evade the CAR-T cells seeking to destroy them.

With a $600,000 grant from the V Foundation through support from Bristol-Meyers Squib, Kara Davis, DO, a pediatric oncologist at the Stanford Cancer Institute, is working to better understand why the leukemia cells take on alternate forms.

“Leukemia cells are very flexible,” Davis says. “In effect, they can say ‘You pressure me and I will change what I look like.’ We want to know whether these alternate forms exist even without the pressure from CAR-T treatments. They might have some other useful function.”

Davis examines healthy cells and leukemia cells in bone marrow to determine which cells express the variant proteins and to what extent. The study could ultimately help researchers improve CAR-T therapy so fewer patients suffer relapses.

“There are a lot of questions that need to be answered about these variants,” says Davis. “If we know that the variants are there before treatment, we might be able to determine who is a good candidate for CAR-T treatment.”

As knowledge increases, new immunotherapies that target alternate forms of the targeted proteins could be developed, says Davis. And as the functions of variant proteins are better understood, they themselves might be a tool to use in future immunotherapies.