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We helped show that two stem cell transplants, plus immunotherapy, significantly increased survival for children with high-risk neuroblastoma.

For years, standard treatment for high-risk neuroblastoma was chemotherapy, radiation and a stem cell transplant. But only about half of the children who received this treatment survived for more than three years afterwards, often because the disease came back. In 2016, a study led by Dr. Julie Park showed that adding a second transplant and an immunotherapy drug significantly increased survival.

The study, which was conducted via the Children’s Oncology Group, showed that 61% of children with high-risk neuroblastoma who received two transplants survived for more than three years, compared to 48% of children who received one transplant. The three-year survival rate jumped to 73% when children received the immunotherapy drug dinutuximab after two transplants. Surviving for three years is a key milestone because most neuroblastoma recurrences strike within three years of treatment.

“These findings were incredibly exciting because they made two transplants plus immunotherapy the new standard of care in North America, and that means more kids will survive,” Park says.

Dr. Julie Park was one of just four researchers invited to give a plenary talk at the American Society of Clinical Oncology Annual Meeting in June 2016.

A “rescue treatment”

Park’s interest in this approach dates back to the late 1990s, when researchers showed that adding an autologous stem cell transplant to chemotherapy helped children beat back neuroblastoma. This approach enabled doctors to target neuroblastoma with chemotherapy regimens that were so aggressive they also destroyed the child’s immune system. The transplant was a “rescue treatment” that helped patients recover.

“When we saw that one transplant worked, a lot of people in the field started wondering if two transplants would be even more effective,” Park says.

After pilot studies showed that two transplants were feasible and tolerable, Park and her colleagues decided to test this approach on a larger scale. They launched their study in 2007 and eventually enrolled 652 children with high-risk neuroblastoma. The median age was 3.1 years old, and the patients were divided into two groups. The first group received chemotherapy and a single transplant. The second group received two chemotherapy regimens, each followed by a transplant.

Drug boosts survival

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Approximately 70% of children in each group were also given dinutuximab after their final transplant. The drug attaches antibodies to neuroblastoma cells, enabling the immune system to recognize and attack them.

“Even the most aggressive chemotherapy can’t kill all the neuroblastoma cells,” Park says. “The goal is for the immunotherapy drug to wipe out some of the cells that are left over.”

Adding the immunotherapy drug boosted the three-year survival rate to 73% after two transplants, compared to 56% after one transplant and immunotherapy.

The results were so promising that Park was one of just four researchers invited to give a plenary talk at the American Society of Clinical Oncology Annual Meeting in June 2016.

Monitoring side effects

Park and her colleagues were especially happy to see that a second transplant didn’t increase children’s risks of severe side effects such as hepatic veno-occlusive disease, a potentially fatal condition that occurs when the liver’s blood vessels become inflamed or blocked.

Park cautions that there are still unanswered questions about the long-term effects of two transplants, but says there’s reason to believe those effects aren’t significantly worse than a single transplant’s toll.

“By the time these patients get to the second transplant, they’ve seen so many drugs that, unfortunately, they’re already going to face potential problems like infertility and hearing loss,” Park says. “Our current information suggests that the tandem transplant doesn’t add to the long-term toxicities, and that it’s a net positive because it significantly reduces the chance of recurrence.”

Less-toxic treatments

Park’s long-term goal is to replace today’s treatments with therapies that are less toxic and more effective. She is leading one of the nation’s first phase 1 clinical trials of T-cell therapies for neuroblastoma. The trial tests T cells, developed by Dr. Michael Jensen, that are programmed to seek out and destroy neuroblastoma cells.

The trial has helped Park’s team make progress toward identifying the ideal dose of T cells to use. Now the researchers are looking for ways to make the T cells better at killing neuroblastoma cells – a difficult proposition because neuroblastoma tumors build a defense system that thwarts immune attacks.

“We’re learning fast and we’re going to keep improving these therapies until we can hopefully cure these kids, with far less chemotherapy and radiation,” Park says.