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New Clues To Why Clinical Outcomes Differ for Neuroblastoma Patients

ARTICLE IN BRIEF

A new study illuminates the role of natural killer cells in neuroblastoma and provides a rationale for targeting specific receptors on those immune cells to potentially treat the often-deadly childhood cancer.

A study from a French research team illuminates the role of natural killer (NK) cells in neuroblastoma and provides a rationale for targeting specific receptors on those immune cells to potentially treat the often-deadly childhood cancer.

The study focused on an NK receptor called NKp30 and its interaction with B7-H6, a cell-surface ligand expressed by neuroblast cells. The researchers found that the profile of the two biomarkers in relation to each other was different for pediatric neuroblastoma patients who fared poorly compared with those who had a favorable outcome.

The findings, which appear in the April 15 online edition of Science Translational Medicine, will likely have no immediate payoff for designing new immunotherapy treatments for neuroblastoma. But they suggest that clinicians, as part of treatment planning, could begin to test for the NKp30/B7-H6 biomarkers to help predict whether a patient is high-risk or low-risk, the study authors said.

Neuroblastoma is the most common extracranial solid pediatric malignancy and it often has metastasized by the time it is diagnosed. It is especially hard to treat in older children with widespread disease. Despite aggressive treatment, only about 30 percent of children older than one year old who have metastatic disease survive, according to the paper.

“Right now we are not always good at classifying patients as having high-risk disease or not,” said John Maris, MD, a pediatric oncologist and neuroblastoma researcher at the Cancer Center for Children at The Children's Hospital of Philadelphia, who was not involved with the current study. “Knowing whether a child is at high risk or low risk for disease recurrence is important because the treatments for neuroblastoma — some combination of chemotherapy, surgery, radiation, high-dose chemotherapy along with autologous stem cell transplantation and immunotherapy — are rigorous.

“We are likely under-treating some and over-treating others,” Dr. Maris told Neurology Today.

The French researchers wanted to examine the question of why high-risk neuroblastoma patients with a similar clinical history — remission of disease after chemotherapy — have different long-term outcomes, with some relapsing and others not.

STUDY METHODOLOGY

Normally, NK cells help keep cancer in check. But previous research has shown that surface antigens on neuroblast cells or soluble proteins can induce an immunosuppressive environment that enables the cancer cells to escape detection.

To understand the specific immune-related mechanisms at work, the researchers set up a retrospective multi-step study involving blood and bone marrow samples collected from a total of 255 children with neuroblastoma: 59 patients for immunophenotyping analysis and 196 for NKp30 isoform profiling.

First, a comparison of samples from children with localized disease compared to those with metastatic disease pointed to the important role that the NKp30 receptor plays in the immune response, said lead author Michaela Semeraro, MD, PhD, a pediatric hematologist-oncologist at Institut Gustave Roussy Cancer Campus in France. The researchers then looked further at the NKp30/B7-H6 connection and found that different isoforms of the NKp30 protein produced different responses.

“If the patient has a favorable NKp30 isoform, A or B, due to genetic polymorphism, the activated NK will produce cytokines against NB cells,” Dr. Semeraro told Neurology Today. In other words, the NK cells recognize B7-H6 on neuroblast cells and mount an attack. Higher levels of NKp30 isoforms A and B were associated with better survival, the study found.

“On the other hand, if the patient presents an unfavorable NKp30 isoform (C), the activated NK cell will produce an immunosuppressant cytokine (IL-10),” causing an immunosuppressant environment that allows the cancer to spread, she said. Higher levels of the C isoform and lower levels of the B isoform were associated with poorer prognosis among the children included in the study, she said.

“We conclude that the interaction between NKp30 and B7-H6 may contribute to the fate of neuroblastoma patients and that both the expression of NKp30 isoforms on circulating NK cells and the concentration of soluble B7-H6 in the serum may be clinically useful as biomarkers for risk stratification,” the researchers concluded.

In addition, “The Nkp30/B7-H6 axis could be a new target for further strategies in the treatment of high-risk neuroblastoma,” said Dr. Semeraro.

EXPERTS COMMENT

Holly Meany, MD, an attending physician and assistant professor in the Division of Oncology at National Children's Medical Center in Rockville, MD, said having a blood test to check certain biomarkers would help physicians to better tailor treatment for patients.

“Perhaps there is a group of patients for which you could spare certain therapies,” said Dr. Meany. If a patient is identified as having a poor prognosis, “you may want to escalate therapy.”

Doctors already use multiple factors to determine whether a neuroblastoma patient is high-risk, including age (patients younger than 18 months do better), stage of tumor, gene status, and tumor pathohistology. But Dr. Meany said that even within the high-risk group, there is variability as to how children respond to treatment.

Dr. Maris, who is also a professor of pediatrics at the University of Pennsylvania, said the exciting part of the French team's research is that it could lead to a therapy in which NK cells are removed from the body and re-educated so that the NKp30 receptors then go back and go after the neuroblastoma.

“That could prevent relapse,” he said. “The paper is helping to better our understanding of how to harness the power of the immune system to cure this disease.”

Varying approaches for revving up the immune system to fight neuroblastoma are in laboratory and clinical testing. The care of children with neuroblastoma got a boost earlier this year when the US Food and Drug Administration approved Unituxin (dinutuximab), an antibody therapy that targets neuroblastoma cells. According to an FDA press release issued in March, 63 percent of study participants receiving Unituxin as part of combination therapy were alive three years later, compared to 46 percent of patients receiving standard treatment. A follow-up analysis found that the drug conferred an advantage.

Melinda Merchant, MD, PhD, clinical director of the National Cancer Institute's Pediatric Oncology Branch, said the French study was important because it highlights the complexity of the interplay between the immune system and neuroblastoma cells, and how NB cells can create a microenvironment that causes NK cells to shift toward immune-suppression rather than their anti-tumor role in immune surveillance.

“It would be good if we could target NK cells and get them into an activation mode rather than an inhibition,” Dr. Merchant said. She said she is involved in an early-stage clinical trial where pediatric and young adult patients have their own NK cells activated in culture and then administered as an immunotherapy with rhIL-15 to try and treat their solid tumors. Other clinical trials are administering NK cells from a parent or sibling to see if they can increase response to anti-GD2 immunotherapy in neuroblastoma, she said.

The French researchers noted that their study had limitations. It included only 196 children from a single country. Most of the participants were Caucasian, and the researchers said it would be useful to study different ethnic populations. They said it would also be helpful to study low-risk neuroblastoma patients who receive chemotherapy to understand their immune response to the cancer.

Dr. Semeraro said in an email that she and her colleagues are continuing to study the role of the NKp30 receptor in cancer.

“Understanding the mechanism of anti-tumor response is crucial to improve and develop new treatments,” she said. “Our findings could be really important to better understand the mechanism of response to immunotherapies (such as anti-GD2 treatment) and to better identify patients who will benefit from these therapies.”

EXPERTS: ON THE UTILITY OF BIOMARKERS FOR NEUROBLASTOMA PROGNOSIS

Figure

DR. HOLLY MEANY said having a blood test to check certain biomarkers would help physicians to better tailor treatment for patients. “Perhaps there is a group of patients for which you could spare certain therapies,” she said. If a patient is identified as having a poor prognosis, “you may want to escalate therapy.”

Figure

DR. JOHN MARIS said the exciting part of the French teams research is that it could lead to a therapy in which NK cells are removed from the body and re-educated so that the NKp30 receptors then go back and go after the neuroblastoma. “That could prevent relapse,” he said. “The paper is helping is to better our understanding of how to harness the power of the immune system to cure this disease.”

Figure

DR. MELINDA MERCHANT said the study was important because it highlights the complexity of the interplay between the immune system and neuroblastoma cells, and how neuroblastoma cells can create a microenvironment that causes natural killer (NK) cells to shift toward immune-suppression rather than their anti-tumor role in immune surveillance. “It would be good if we could target NK cells and get them into an activation mode rather than an inhibition,” she said.

LINK UP FOR MORE INFORMATION:

•. Semeraro M, Rusakiewicz S, Minard-Collin V, et al. Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients http://stm.sciencemag.org/content/7/283/283ra55. Sci Transl Med 2015: 7(283): 283ra55.