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• Posted April 6, 2023

CAR-T Therapy Helps Kids Battling Deadly Nervous System Tumors

A therapy that arms the immune system to find and destroy tumor cells has shown early promise against a rare and aggressive childhood cancer.

Experts called the findings "promising." But they cautioned that much larger studies are needed to see whether and how the treatment can fit into battling the cancer, called neuroblastoma.

Neuroblastoma begins in immature nerve cells, with tumors usually first apparent in the abdomen. It primarily affects babies and children younger than 5 years. Each year in the United States, about 800 children are diagnosed with the disease, according to the American Cancer Society.

Roughly half of those kids are diagnosed after the cancer has spread and is considered "high risk."

At that point, aggressive treatment is needed. The typical regimen starts with high-dose chemotherapy, followed by surgery to remove any remaining visible tumors. Next comes more chemo, a stem cell transplant to rebuild the battered immune system, and then radiation.

In more recent years, doctors have added another weapon to the end of that regimen: the monoclonal antibody drug dinutuximab. The drug latches onto GD2, a protein on the surface of many neuroblastoma cells. It's given along with certain immune system proteins, in the hopes of boosting the child's immune response to cancer cells that have survived the treatment onslaught.

Despite it all, many children still succumb to the disease. Around 40% to 50% of kids are still alive and recurrence-free five years later, according to the researchers on the new trial, from Bambino Gesù Children's Hospital in Rome.

Their results were published April 6 in the New England Journal of Medicine.

The study included 27 children with especially difficult cases of high-risk neuroblastoma. Their cancer had either come back or was not responding to initial treatments. About half had received dinutuximab.

The researchers tried a tactic that has worked very well for some aggressive cases of blood cancer, but is not yet proven for other types of cancer: CAR T-cell therapy.

Like dinutuximab, CAR T-cell therapy enlists the immune system, but in a much different way: Doctors remove a sample of a patient's T cells, then genetically alter them to be armed with chimeric antigen receptors, or CARs.

Those CARs allow the T cells to recognize certain markers on the surface of specific cells that are no good -- like cancer cells. Once the T cells are infused back into the patient, they can launch a targeted attack on the enemy cells.

In this trial, the children's T cells were equipped to recognize the neuroblastoma protein GD2.

Within six weeks of treatment, 63% of the children responded, meaning their cancer at least partially regressed. Nine children, or one-third, showed no signs of the disease -- though four later relapsed.

After three years, 40% of all kids in the trial were still alive, but survival was higher -- 60% -- in the small subgroup given the highest CAR T-cell dose.

"From these results, it looks promising. But this is a small study, and the follow-up was three years," said Dr. Rani George, a pediatric hematologist/oncologist at Boston Children's Hospital/Dana-Farber Cancer Institute.

Larger trials are needed before CAR T cells could become a "widely accepted" treatment for this disease, according to George, who was not involved in the trial.

It's not clear, she said, whether it could actually be more effective than today's standard therapy with dinutuximab.

It's possible, George noted, that CAR T cells might avoid some side effects of the antibody, including pain. Or the cell therapy could be an option when children do not respond to dinutuximab.

But that all remains to be seen, George said.

CAR T cells can have their own serious side effects. A major one is cytokine release syndrome -- where the infused T cells flood the bloodstream with chemicals called cytokines, which can trigger problems like high fever and sharp blood pressure drops. Severe cases can be fatal.

Most of the children in this trial, George noted, developed cytokine release syndrome, though nearly all were mild cases.

As a safety measure, the Italian team outfitted the CAR T cells with an "off switch" -- a gene that, when activated by medication, causes the T cells to kill themselves, to hopefully halt severe side effects.

In theory, that could treat dangerous cases of cytokine release syndrome, according to Drs. Oladapo Yeku and Dan Longo, of Massachusetts General Hospital Cancer Center and Harvard Medical School.

They wrote an editorial published with the study.

In it, they call the safety and efficacy of the therapy "favorable," but also point to the need for bigger studies. One important goal, they wrote, is to understand why some children with neuroblastoma respond to CAR T cells, but others don't.

More information

The American Cancer Society has a primer on neuroblastoma.

SOURCES: Rani George, MD, PhD, pediatric hematology/oncology, Boston Children's Hospital/Dana-Farber Cancer Institute, and professor, pediatrics, Harvard Medical School, Boston; New England Journal of Medicine, April 6, 2023