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In 2017, Stephanie Uy learned that her 22-month-old daughter, Aspen, had stage IV high-risk neuroblastoma.

The cancer, which develops from the sympathetic nervous system, is the most common type of solid tumor in children outside of the brain. Patients with high-risk neuroblastoma tend to be older than 18 months at diagnosis, have amplification of the MYCN gene, and often have metastatic disease. Their treatment involves a prolonged sequence of chemotherapy, surgery, high-dose chemotherapy with stem cell rescue (HDC-SCR), radiation, and immunotherapy. Even then, only about half of children survive.

In the Philippines, where Uy and her family lived, Aspen’s treatment plan comprised chemotherapy, surgical resection of the primary tumor on her adrenal gland, HDC-SCR, and radiation. But that was it: The lifesaving immunotherapies that had become standard in the United States, Europe, and parts of Asia for high-risk patients were not yet available in the Philippines.

Before Aspen underwent her first round of chemotherapy, Uy and her husband gave their daughter a new name. One tradition in the Philippines holds that changing the name of a sick person can change his or her fate, Uy explained in an interview. Aspen, who loved singing along to the movie “The Sound of Music” with her family, became Maria, after the movie’s heroine.

After more than a year of hospitalizations and harsh treatments, Maria was still not cancer-free. Uy quietly resolved to make Maria’s life as happy as possible for whatever remained of it, taking her to toy stores and the aquarium and on a pilgrimage to her hometown.

But Maria’s fate changed when Uy learned that St. Jude Children’s Research Hospital in Memphis, Tennessee, was conducting studies in children with refractory high-risk neuroblastoma and that Maria fit the criteria for inclusion. “At the time we didn’t even know what St. Jude was,” Uy said in an interview. “But I said, ‘of course we’re interested.’”

A Rare Mutation Offers Opportunity

Sara Federico, MD, of St. Jude, the lead investigator on the study, had been studying neuroblastoma for more than a decade and leading clinical trials. In recent years, Federico and her colleagues had shown the value of immunotherapy with antibodies against GD2, a key cell surface protein in neuroblastoma, at the end of the treatment sequence in high-risk patients. They also found that induction therapy combining chemotherapy with anti-GD2 antibodies further improved outcomes.

In 2019, when Maria first arrived at St. Jude, “we administered chemoimmunotherapy, as she had not previously received this combination of therapy. While she demonstrated a partial response, she still had a significant disease burden in her bone marrow,” Federico said. The implications of treatment failure were grave; patients with refractory disease to treatment have poor 5-year survival.

While Maria was receiving chemoimmunotherapy, genomic testing was performed and revealed that Maria carried a relatively rare genetic mutation on the BARD1 gene. This suggested that her cancer might respond to a different approach.

Mutations are not as common in neuroblastoma as in adult solid tumors — “in general, neuroblastoma has a quiet genome,” Federico said — but when they do occur, they can present important opportunities to intervene. “For Maria, we identified that she had a potentially actionable mutation, so we developed a plan to target it.”

BARD1 mutations, also seen in some breast cancers, can respond to a class of drugs called poly(ADP-ribose) polymerase (PARP) inhibitors, which interrupt the DNA repair process of cancer cells. Maria received an experimental combination of talazoparib, a PARP inhibitor, and irinotecan, a chemotherapy drug.

Maria is now a cancer-free 9-year-old doing well in school. This treatment success was the first of its kind, leading Federico and her colleagues to publish the case last year in a letter to The New England Journal of Medicine. Building on this success, Federico and her team are now studying the combination of a PARP inhibitor plus chemotherapy in pediatric patients with gene mutations related to DNA repair defects.

“The fact that Maria responded to this therapy and has been off treatment for years without any evidence of disease is really exciting,” Federico said. “It highlights the significant variability across the diagnosis [of neuroblastoma] and also the fact that success in this field is dependent on multiple research directions and treatment approaches.”

While BARD1 mutations like Maria’s are rare in neuroblastoma, other mutations can be found in the ALK gene. These occur in about 15% of cases and can also be targeted with existing therapies.

Early Chimeric Antigen Receptor (CAR) T Cell–Treated Patient Now a Healthy Adult

In February of this year, a research group at Baylor College of Medicine and Texas Children’s Hospital in Houston reported the remarkable case of a woman who is alive and well 18 years after receiving experimental CAR T-cell therapy for the refractory neuroblastoma she presented with as a young child.

CAR T cells are made by genetically altering a patient’s own T cells, which are unique cells of the immune system that develop in the thymus, to express specific antigen receptors (receptors specific to GD2, in the case of neuroblastoma).

This allows the CAR T cells to recognize and attack cancer cells more effectively. CAR T-cell treatments have produced durable long-term remission in patients with leukemia and other blood cancers, but CAR T’s role in treating certain solid tumors, including neuroblastoma, is still being investigated.

The strategy for treating neuroblastoma with CAR T cells was first developed by Baylor investigators Malcolm Brenner, MD, PhD; Helen Heslop, MD; and Cliona Rooney, PhD, who tested it from 2004 to 2009 in patients with high-risk neuroblastoma.

The former patient, who received treatment as a child as part of that study, has given birth to two healthy children and remains disease-free. Her case represents the longest known survival to date of any patient with cancer treated with CAR T cells. Of the 11 patients with active disease who received CAR T treatment, two saw a sustained response — the woman and another patient who remained healthy for 8 years before being lost to follow-up. The rest have since died.

Baylor researcher Andras Heczey, MD, who was not part of the original CAR T trial but works closely with its investigators, said that the long-term follow-up findings “really demonstrate that [neuroblastoma] patients can be cured with a single CAR T-cell infusion,” even with a first-generation CAR T therapy, as was used in the 2004-2009 study.

“We need to have survivors,” Heczey said. “Right now, the big question is, how can we go from a handful of patients who are long-term survivors to a reliable expectation where the majority of patients will reach durable, complete remissions?”

Research groups around the world are working to provide answers. At Heczey’s lab, one idea has been to improve CAR T for neuroblastoma patients. Early this year, his group published a paper describing a novel mechanism for helping CAR T cells to proliferate and attack solid tumors more effectively.

“Newer-generation therapies hold tremendous promise for these children,” Heczey said.

CAR T therapy can cause what is known as cytokine release syndrome, a systemic inflammatory response. And for patients with neuroblastoma already exposed to a series of toxic therapies, limiting toxicity is of particular concern.

In 2023, a group of researchers in Italy tested GD2 targeting CAR T that had been engineered with a so-called suicide gene, which acts as a “safety switch” allowing the cells to be killed if they produce severe adverse effects. Not only was the approach shown to be safe in high-risk refractory or relapsed neuroblastoma patients, but one third of them saw a complete response, the investigators reported, suggesting further possibilities for CAR-T in neuroblastoma treatment.

Federico said she hopes that an improved CAR T might emerge as an important addition to the treatment arsenal.

“I think there’s a subset of patients that will respond well to this therapy,” she said; the trick will be to identify them.

Other types of immune cells are also being investigated for use in high-risk neuroblastoma. These include natural killer T (NKT) cells, which “have an indirect way of controlling tumor growth,” Heczey explained. NKT cells attack what are called tumor-associated macrophages, or white blood cells that infiltrate a tumor and help it to grow.

Heczey and his colleagues engineered CAR-NKT cells that can directly target cancer cells while maintaining their ability to attack the macrophages, offering a two-pronged approach. In 2023, they published results from a trial in 12 children with neuroblastoma, of whom five saw a treatment response and one had “a reasonably durable complete response,” Heczey said.

A Nimble, Diverse Research Climate

Most clinical trials in high-risk neuroblastoma are small, early-phase studies. Key in this effort are networks of participating research hospitals, such as the New Approaches to Neuroblastoma Therapy (NANT) consortium, which was formed in 2000. The consortium includes St. Jude and more than a dozen other institutions in the United States and Europe.

“Many of the improvements we’ve seen for patients with high-risk neuroblastoma started in cooperative groups such as NANT,” Federico said. By facilitating more trials in patients with relapsed or refractory neuroblastoma, promising agents and approaches can be identified before being tested in larger phase 3 studies.

Heczey said the collaboration efforts have resulted in an exceptionally nimble research climate in neuroblastoma. Collaboration “is what is letting us enroll enough patients on a given trial fast and get the answers. If things work, fantastic. If not, we want to know why they didn’t work right away so we can move on and test the next idea.”

At the Advances in Neuroblastoma Research Meeting in Washington, DC, in late May, the diversity of global research will be on display. Highlights include new CAR applications, novel immunotherapeutic targets, harnessing different types of immune cells, and more mutation-specific approaches.

Results from recent clinical trials will be presented, as well as follow-up from older ones. Each new story of long-term survival adds to the excitement, the investigators said.

One important caveat is that most of the major advances in neuroblastoma treatment, including the cell therapies like CAR T, have come through federally funded academic research, which is broadly under threat. The NANT consortium recently published a statement of concern about funding cuts to institutions supported by the National Institutes of Health (NIH).

Heczey acknowledged that maintaining momentum will prove a challenge if NIH funding is severely curtailed. “I hope we will continue to see NIH support and also bring in more philanthropic funding and foundations,” he said. “Fortunately, we also have a strong pediatric advocacy group presence in neuroblastoma. I think we are going to see some exciting improvements in the years to come.”

Heczey disclosed holding patents related to the NKT cell platform, CAR design, cytokine co-expression, and other genetic engineering processes. He also has consultancy agreements with Waypoint Bio and Kite Pharma. Federico disclosed no financial relationships.