Cornering a Cancer-Connected Autoimmune Disease

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It is certainly not good news for children to get a double whammy of both cancer and autoimmune disease. Unfortunately, for a small subset of children with neuroblastoma, a common childhood cancer of the peripheral nervous system, an extremely rare autoimmune disorder called Opsoclonus Myoclonus Ataxia Syndrome (OMAS) comes along for the ride. The overactive immune response is believed to be triggered by the cancer.

But there is a twist.

“Patients with neuroblastoma who have OMAS have better outcomes, in terms of their tumor, than patients with neuroblastoma who don’t have OMAS,” said Jessica Panzer, MD, PhD, a pediatric neurologist and attending physician at The Children’s Hospital of Philadelphia who is studying this disease.

That pattern leads Dr. Panzer and other researchers to wonder: Is it possible that OMAS is a case of the body’s immune system finding a successful defense against cancer (but taking it a little too far against healthy cells)? And could we learn safe ways to harness its ability to help more children with neuroblastoma, or even other cancers?

These are among many long-term questions on the distant horizon for researchers who study this little-understood autoimmune disease. First, they need to understand the basics.

Little is known about the underlying biology of OMAS even though the condition has been known for more than 50 years. Only about 3 percent of neuroblastoma patients develop OMAS — accounting for about half of OMAS patients overall. Many clinicians will never encounter a patient with its characteristic jerky eye movements, known as opsoclonus. Because the condition involves immune cells attacking areas of the brain that affect balance and movement, children with OMAS can have chronic challenges with movement, speech, and coordination. Mood and behavioral complications, such as crankiness, are also common.

Dr. Panzer has teamed up with Miriam Rosenberg, PhD, of the Weizmann Institute of Science in Israel, for a new research collaboration to better understand the basic mechanism of what triggers OMAS in children with neuroblastoma. It is a critical first step toward better treatments and new insights into both OMAS and neuroblastoma. They received a grant earlier this year from the Pablove Foundation to begin their work together.

Imaging the Antigen

Dr. Panzer’s part of the project is aimed at finding the antigen — some chemical on the surface of nerve cells — that triggers the autoimmune response in OMAS. She will use serum samples from patients with neuroblastoma and OMAS and expose them to in vitro rodent neuron cells, from the types of healthy brain tissue that are under attack in OMAS.

This is a technique developed by researchers from the University of Pennsylvania and CHOP that previously successfully identified the antibody underlying a severe form of encephalitis. When antibodies or other substances in the serum bind to the surface of the neurons, this technique will light up their union. Comparing the interactions of healthy neurons with the OMAS patients’ serum, to neurons’ interactions with various control samples, Dr. Panzer hopes to find the spots lighting up for a compound that is unique to OMAS patients. Preliminary findings from a pilot study published this summer are pointing her in the right direction.

Secrets in the Sequencing

Meanwhile, Dr. Rosenberg is looking at samples from patients’ tumors to find out what the immune system is doing inside neuroblastoma tumors in children with OMAS. Few people have looked in this comprehensive way before.

“Little is known about the immune profile of neuroblastoma,” Dr. Rosenberg said. “Even less about this rare subset with OMAS. Maybe there is something special in these kids that is helping them to contain the neuroblastoma.”

On the hunt for that possible “something special,” Dr. Rosenberg will look at the tumors’ genomic DNA to identify sequences that match the characteristic mature pattern of the immune system’s T-cell receptors. She also will look at the sequence of the mRNA molecules in the tumor cells to find out which proteins and non-coding RNAs are expressed in those cells.

If there are unique T-cell receptor DNA signatures or differentially expressed genes in the OMAS patients’ tumors, compared to non-OMAS patients’ tumors, then Dr. Rosenberg might be on the trail of the antigen that triggers the autoimmune disease.

Outcomes Uncertain

The researchers hope that by casting a wide net, eventually this research will contribute to an antibody test to identify OMAS clinically without relying solely on symptoms. Such a test also could quantitatively track patients’ progress while in treatment for the disorder —something that is hard to do based on symptoms alone, when that judgment entails monitoring a toddler’s motor coordination. A targeted therapy for OMAS would be an even better long-term outcome, as would potential insight that OMAS research might offer into new cancer treatments.

A long road lies ahead. But, Dr. Panzer said, “You can’t get anywhere down the road without understanding the very first step. That’s where we are.”

To read more about the story behind Dr. Panzer’s collaboration with Dr. Rosenberg, and how both scientists became interested in studying OMAS, read the post on Cornerstone, the CHOP Research Institute blog.

Since 2010, The Pablove Foundation has awarded more than $1,150,000 in Childhood Cancer Research Grants to 16 institutions worldwide. Their researchers are searching for more effective treatment options, and for a better understanding of how childhood cancers behave. To learn more, visit the Pablove Foundation grants page.

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