Rewriting the Rules

More precise, less toxic cancer therapies aren’t a futuristic vision anymore – they’re saving kids today.

Daisy and AliyannahAliyanna Martinez had two surgeries to remove malignant tumors before she was 8 weeks old – only to have the cancer quickly start growing back. When her doctors in Portland recommended chemotherapy, Aliyanna’s parents thought it was her last, best hope. Then they learned that Seattle Children’s was testing a more precise, less toxic alternative – a drug called larotrectinib that counteracts the genetic flaw driving Aliyanna’s cancer.

Aliyanna flew here to receive the drug in February. Her tumors had nearly disappeared by April.

“It felt like a miracle,” says her mother, Daisy Martinez. “We went from thinking we might lose her any day to having a smiling, happy 5-month-old.”

It’s just one of the ways researchers at Seattle Children’s are rewriting the rules of childhood cancer treatment to make it less toxic and more effective – and to give kids a better chance at a healthy life.

“Things like personalized medicine and using the immune system to fight cancer aren’t a futuristic vision anymore,” says Dr. Doug Hawkins. “We’re getting closer to the day when some patients may need far less chemotherapy and radiation.”

Tailored treatments

When Hawkins started his career in 1990, most cancer research studies explored how chemotherapy drugs could be applied to more cancers or combined to be more effective. Even as these drugs dramatically improved survival, they triggered debilitating side effects like learning disabilities, hearing and growth problems, and increased risk of heart disease and future cancers. And they didn’t work for some children at all.

“The game needed to change,” Hawkins says.

Now Seattle Children’s is part of a revolution to develop therapies that try to directly kill cancer cells, with minimal impact on the rest of the body. Hawkins and his colleagues, for instance, are part of a nationwide push to develop an approach called personalized medicine. The goal is to pinpoint the mutation that made the patient’s tissue turn cancerous and then deliver a drug that disarms that mutation and stops the cancer.

“The idea is to tailor the treatment to each patient’s tumor, instead of blasting the body with chemotherapy or radiation,” Hawkins says.

Breakthrough drug

Now we’re participating in the first studies to investigate whether these drugs are effective in children – including the clinical trial of larotrectinib. Hawkins helped to design the trial’s pediatric arm, and we’re one of several hospitals participating in it.

Larotrectinib targets a mutation, called a TRK fusion, that drives rare cancers like infantile fibrosarcoma and thyroid carcinoma. A landmark paper co-authored by Hawkins earlier this year showed that 93% of children with the TRK mutation responded to larotrectinib.

Ashton Leeds, 9, is one of those kids. His thyroid cancer had spread into his lungs until he couldn’t breathe without extra oxygen.

“Our doctors told us that Ashton was out of options,” says his mom, Kayley Leeds. “All we could do was hope that treatments advanced or that there was a research breakthrough.”

When the family learned that Ashton was a candidate for larotrectinib, they flew to Seattle from their home in Calgary. His tumors shrank dramatically. Now Ashton is back to running around with his friends and playing soccer again.

“It’s amazing to see kids like Ashton transform so quickly, and it motivates us to keep exploring innovative treat-ments for other cancers,” says Dr. Katie Albert, who oversees the larotrectinib trial at Seattle Children’s.

Replacing chemotherapy

Hawkins and his colleagues at the Children’s Oncology Group are designing a study that will offer larotrectinib as initial treatment for kids with the TRK mutation. The Children’s Oncology Group is a research consortium that unites experts from around the world to study cancer and search for cures.

“If larotrectinib can help some kids right when they’re diagnosed, then many of them won’t need surgery, chemo-therapy or radiation,” Hawkins says.

Donors make it possible

Clinical trials are the final step of bringing therapies from the lab to the clinic, but they’re expensive and traditional funding only covers about a third of the cost per patient. Donations to our cancer clinical trials fund help fill that gap.

This philanthropy will be especially important as researchers pursue personalized treatments for a wider range of cancers. Hawkins cautions that these treatments have a long way to go because researchers are learning that some mutations don’t respond to targeted drugs. He and his colleagues are mulling ways to make these drugs more effective by modifying them or combining them with existing therapies.

“In research, you learn pretty fast that there aren’t any magic bullets – you make progress by methodically tackling new problems,” Hawkins says. “Personalized treatments might not be the answer for every pediatric cancer, but every time we learn something it brings us closer to the right approach.”

Developing immunotherapies

Dr. Michael Jensen is leading our cancer immunotherapy charge.

“T cells are the immune system’s warriors and we want to harness that power and turn it against cancer,” Jensen says.

He was among the first researchers to start genetically reprogramming T cells to destroy cancer cells. His work helped prove that this approach could wipe out cancer in the lab. Today, we’re among a small handful of institutions that are turning immunotherapy into a real-world cure – and we have more immunotherapy studies for more types of cancer than any other program in the country.

These studies saved Milton Wright III from leukemia after he relapsed twice and was out of options. In 2013, Milton became the second patient in our first cancer immunotherapy clinical trials. The therapy wiped out his cancer; today he’s 25 and works as a nursing assistant in our intensive care unit.

“It’s amazing to be able to help kids at the hospital where I got treated,” he says.

Pursuing long-term cures

Milton’s not alone: 93% of those who participated in our first immunotherapy clinical trial achieved remission. But cancer is tricky, and half those patients saw their leukemia come back within a year. It’s not that immunotherapy doesn’t work. It simply means that there’s more work to be done to develop a permanent cure.

With critical support from Strong Against Cancer – a key fundraising priority of It Starts With Yes: The Campaign for Seattle Children’s – Jensen’s team is launching clinical trials of new T-cell therapies that aim to prevent these kids from relapsing and to target many other cancers.

We recently launched the first-ever trial that delivers modified T cells directly to pediatric brain tumors. We’re also launching a new generation of immunotherapies that target neuroblastoma, one of the deadliest childhood cancers.

“We’re learning fast and we’re going to keep improving these therapies until we can cure kids for good,” Jensen says.

Originally published in Connection magazine, Fall 2018.