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When Michelle Monge was a medical student 20 years ago, she saw her first case of diffuse intrinsic pontine glioma, a childhood brain cancer that is almost always fatal within a year. Monje decided to study the disease further — “I just couldn’t turn away” — but several senior faculty members tried to dissuade her.
They “were concerned that there was little interest because the disease was so rare and that I would struggle to achieve anything,” she recalls.
Such was the state of pediatric cancer research at the time. But the field has undergone remarkable change in the past decade.
Today, armed with data from technological advances and pressured by parental advocates, scientists are exploring new strategies to treat childhood cancers. They involve manipulating immune system cells, proteins and other molecules to design targeted therapies that they believe will be more precise and less toxic than conventional chemotherapy.
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Although cancer is rare in children, it is still the leading cause of death from disease. Last year, the National Cancer Institute (NCI) predicted 10,500 new cases in children from birth to age 14 in 2021, with 1,190 deaths, although some experts believe the number is likely higher. The most common childhood cancers include leukemias, brain and other central nervous system (CNS) tumors, and lymphomas, according to the NCI.
Kathryn Bollard, director of the Center for Cancer Research and Immunology at Children’s National Hospital Research Institute in D.C., acknowledges that there are more older cancer patients, a long-standing reason why drug companies favor researching their drugs. But treating children has a long-lasting effect.
“The children who survive will be productive citizens for a longer time than an adult you’re trying to give an extra five years to,” she says.
Pediatric oncologists applaud the recent progress, adding that the momentum must continue.
“These changes in recent years have spurred approaches that are beginning to have a real impact on improving the care and outcomes of children with diseases that were considered incurable 10 years ago,” said Paul Sondel, the Reed and Carolee Walker Professor of Pediatric Oncology at the University School of Medicine and Public Health in Wisconsin and a pediatric oncologist for more than 40 years. “However, even though we are seeing new progress, we know there is still a long way to go before we can cure all children with cancer.”
Dina Singer, a senior investigator in the National Cancer Institute’s Experimental Immunology Branch and chief of NCI’s Division of Molecular Regulation and deputy director for scientific strategy and development, agrees, but she insists that scientists’ commitment to children has never wavered , only previous challenges have been great.
Today, scientists know much more about childhood cancers than ever before.
“We’ve always had a long-standing, ongoing interest in pediatric cancer,” she says. “What has changed is our understanding of how fundamentally different childhood cancers are from adult cancers, which has opened up new [research] opportunities.”
“Children are wired differently”
Pediatric cancers are unique and cannot be treated like adult cancers, experts say.
“Kids are wired differently,” says Crystal McCall, the Ernest and Amelia Gallo Family Professor of Pediatrics and Internal Medicine at Stanford University and former chief of NCI’s Pediatric Oncology Branch. “Old people acquire a lot of cell mutations, step by step,” which is why most people who get cancer are older. “Children’s cancers are more like a switch—boom—and turning that switch off is difficult because their cancers are not molecularly the same.”
Bollard agrees. “There’s this assumption that we can just take drugs that work in adult cancers and they’ll work in children,” she says. “This is not right. We cannot rely on therapeutic approaches to trickle down.”
Although chemotherapy is effective against childhood blood cancers such as acute lymphocytic leukemia (ALL)—the most common childhood leukemia—it is less successful against solid tumors. Additionally, children receiving chemotherapy and radiation are at risk of serious health consequences later, including new cancers and heart and lung problems, among others.
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“We don’t worry about long-term side effects in 70- or 80-year-olds, but we have to worry about them in children,” says Douglas Hawkins, MD, professor of hematology-oncology at Seattle Children’s Hospital and chairman of the Children’s Oncology Group, funded by from the NCI consortium of more than 200 hospitals treating and studying children with cancer. “If we cure a 3-year-old’s cancer, it’s not to extend his life for a few months, but for a lifetime. The benefits to society are enormous.”
NCI spending on pediatric cancer research rose from 5.57 percent of its budget in fiscal 2016 to 8.77 percent in fiscal 2021, according to the institute. Also, the National Institutes of Health, of which the NCI is a part, invested about $664 million in childhood cancer research in fiscal 2021, an increase of $85 million from fiscal 2020, according to the NCI. NCI’s total budget for fiscal year 2021 was nearly $6.4 billion.
Scientists welcome the boost, but say they could still use more. “It’s a useful increase, but it’s still not enough to have the impact that childhood cancer really needs, especially given the years of life that could potentially be saved,” says Sondell.
Monje, now a pediatric neuro-oncology researcher and physician at Stanford University, ignored that long-held advice and stuck to his plan.
She and McCall are developing a cell-based immunotherapy known as CAR (chimeric antigen receptor) T cells to treat the brain tumor that so frustrated her as a medical student. Early results are encouraging.
The technique involves removing immune T cells from the patient, engineering them in the lab to recognize cell markers abundant in tumors, then returning them to the patient. The altered cells include a protein – CAR – that does not occur in nature. The CAR protein binds to the tumor and stimulates the created T cells to multiply, then attack and kill the cancer cells.
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Although it is not yet cured, Monje and Mackall are excited by the behavior of the cells and plan to tune them further. “It’s still early, and I don’t want to overstate it, but given that this is a disease where nothing has worked, it’s unbelievable,” says Macal.
“These CAR T cells are so specific that they just go into the tumors,” says Monje. “We see a response within weeks of their significant improvement symptomatically. We have seen children go from wheelchairs to walking in two weeks. Even though the cancer came back, three of the first four children we published had a great response to treatment.”
Giving a second dose led to improvements, and the team now administers monthly infusions, hoping they will provide a more durable response, Monje says. They plan to further modify the cells and will test them in the lab before giving them to patients.
As with most scientific advances, the steps are incremental, she says. “This process of iteration, from bench to bedside, then from bedside to bench, over and over again, is how we’re ultimately going to cure diffuse intrinsic pontine glioma,” she says.
CAR T products are approved to treat certain blood cancers in adults and children, but not solid tumors. They are more resistant to therapy, possibly because malignant cells in blood cancers are more accessible to wandering CAR T cells, cancer experts say.
Bollard, along with Martin Poole of the UCL Cancer Institute at University College London, recently received around $24 million from the Cancer Grand Challenges program, funded by the NCI, Cancer Research UK and the Mark Foundation for Cancer Research, to research the hard-to-treat childhood cancer solid diseases tumors. They are also investigating the use of CAR T cells.
They manipulate CAR T cells to make a protein that can block transforming growth factor beta (TGF-beta), “a nasty cytokine that has devastating effects on the ability of T cells to grow and kill tumors,” Bollard explains . (Cytokines are small proteins that influence the activity of immune system cells.) “Most human cancers use TGF-Beta to evade the immune system,” Bollard says, adding that the idea is to “boost” CAR T , to thwart this cytokine.
“We want CAR T to become the standard of care within a decade for children with these solid tumors,” she says.
Targeted therapies like CAR T represent the “next revolution” in treating childhood cancers, says Andrew Kung, a pediatric oncologist who heads the division of pediatrics at Memorial Sloan Kettering Cancer Center in New York. “We are very excited about their potential pediatric applications,” he says.
He cited antibody-based therapies as additional promising approaches, including antibody drug conjugates and “bi-specific” antibodies.
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Conjugates are monoclonal antibodies — lab-made proteins that latch onto specific targets, such as antigens (foreign substances in the body) on cancer cells — that are chemically linked to drugs. The antibodies release the drugs that kill the cancer cells without harming other cells. “Bi-specific” antibodies contain two arms, one that binds to cancer cells, the other to T cells and deploys them to fight the cancer.
Experts point out that the technological advances that underpin these therapeutic advances do not fully explain the current resurgence. They praise the work of parent advocacy groups; the desire of hospitals and academic institutions to…
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