Comment When Michelle Monje 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 walk away”—but several senior faculty members tried to dissuade her. “They were worried that there was little interest because the disease was so rare and that I would struggle to achieve anything,” he recalls. This was the state of childhood cancer research at the time. But the field has undergone a remarkable change in the last decade. Today, armed with data from technological advances and pressured by parental advocates, scientists are exploring new strategies to treat childhood cancers. These involve manipulating cells, proteins and other molecules of the immune system to design targeted therapies that they believe will be more precise and less toxic than conventional chemotherapy. My daughter died of brain cancer. Here’s what we can do to save other children. Although cancer is rare in children, it is still the leading cause of death from the 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 types of childhood cancers include leukemias, brain and other central nervous system (CNS) tumors, and lymphomas, according to the NCI. Catherine Bollard, director of the Center for Cancer and Immunology Research at the Children’s National Hospital Research Institute in DC, acknowledges that there are more adult cancer patients, the long-standing reason drug companies have favored researching drugs in them. But treating children has a long-lasting impact. “Children who survive will be productive citizens for a longer period of time than an adult you’re trying to give an extra five years to,” he says. Pediatric oncologists applaud the recent progress, adding that the pace must continue. “These changes in recent years have led to 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,” says Paul Sondel, the Reed and Carolee Walker Professor of Pediatric Oncology at the University. of the Wisconsin School of Medicine and Public Health and a pediatric oncologist for more than 40 years. “However, while we are seeing new progress, we know there is still a long way to go before we can cure all children with cancer.” Dinah Singer, a senior researcher in the National Cancer Institute’s Division of Experimental Immunology and chief of NCI’s molecular regulation division and associate director for scientific strategy and development, agrees, but insists that scientists’ commitment to children has never wavered, except that the previous challenges were terrible. Today, scientists know much more about childhood cancer than ever before. “We’ve always had a long-standing ongoing interest in pediatric cancer,” he says. “What has changed is our understanding of how fundamentally different childhood cancers are from adult cancers, which has opened up new [research] chances.”
“Children are wired differently” Childhood cancers are unique and cannot be treated like adult cancers, experts say. “Kids are wired differently,” says Crystal Mackall, the Ernest and Amelia Gallo Family Professor of Pediatrics and Internal Medicine at Stanford University and former chief of NCI’s Division of Pediatric Oncology. “Adults acquire many cell mutations, step by step,” which is why most people who get cancer are older. “Childhood cancers are more like a switch—boom—and turning off that switch is difficult because their cancers are not molecularly the same.” Bollard agrees. “There was this assumption that we can just take drugs that work on adult cancers and they will work in children,” he says. “This is not right. We can’t rely on drip treatments.” While chemotherapy was effective against childhood blood cancers such as acute lymphocytic leukemia (ALL)—the most common childhood leukemia—it was less successful against solid tumors. In addition, children who receive chemotherapy and radiation are at risk of serious health effects later, including new cancers and heart and lung problems, among others. Live Like Lola: A girl makes the most of life while battling a brain tumor “We don’t worry about long-term side effects in a 70- or 80-year-old person, but we have to worry about them in children,” says Douglas Hawkins, professor of hematology-oncology at Seattle Children’s Hospital and chairman of the Children’s Oncology Group, a consortium funded by the NCI of more than 200 hospitals that treat and study children with cancer. “If we treat cancer in a 3-year-old child, it is not to extend his life for a few months but for a lifetime. The gains for society are huge.” NCI spending on pediatric cancer research increased 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 over fiscal 2020, according to the NCI. NCI’s total budget for fiscal 2021 was nearly $6.4 billion. Scientists welcome the boost, but say they could still use more. “This is 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 Sondel. Monje, now a pediatric neuro-oncology researcher and physician at Stanford University, ignored that old advice and stuck to her plan. She and Mackall 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, and then returning them to the patient. The altered cells include a protein – CAR – that does not exist in nature. The CAR protein binds to the tumor and stimulates the modified T cells to multiply, then attack and kill the cancer cells. Cancer Report Shows Patients Face a Difficulty Beyond the Disease: Bill Zooming Although not yet therapeutic, Monje and Mackall are excited by the cells’ behavior and plan to improve them further. “It’s still early days and I don’t want to overstate it, but given that this is a disease where nothing has worked, it’s incredible,” says Mackall. “These CAR T cells are so specific, they just go into the tumors,” says Monje. “We see a response within weeks of getting much better symptomatically. We have seen children go from wheelchairs to walking in two weeks. Although the cancer came back, three of the first four children we published had a great response.” Giving a second dose brought improvements, and now the team is giving monthly infusions, hoping they will provide a more durable response, Monje says. They are planning further modifications to the cells and will test them in the lab before giving them to patients. As with most scientific progress, the steps are incremental, he says. “This process of repetition, from bench to bed, then bed to bench, over and over again, is how we’re ultimately going to treat diffuse native mucoid pontius,” he says. CAR T products are approved to treat certain blood cancers in adults and children, but not solid tumors. These are more resistant to treatment, possibly because malignant cells in blood cancers are more accessible to wandering CAR T cells, cancer experts say. Bollard, along with Martin Pule of the UCL Cancer Institute, University College London, recently received around $24 million from the Cancer Grand Challenges programme, funded by the NCI, Cancer Research UK and the Mark Foundation for Cancer Research, to to study the hard-to-treat child material. volumes. 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 affect the activity of immune system cells.) “Most human cancers use TGF-Beta to evade the immune system,” says Bollard, adding that the idea is to “turn on” the CAR T to block this cytokine. “We want CAR T to become the standard of care within a decade for children with these solid tumors,” he says. Targeted therapies like CAR T represent “the next revolution” in treating childhood cancers, says Andrew Kung, a pediatric oncologist who chairs the pediatric division at Memorial Sloan Kettering Cancer Center in New York. “We are very excited about their potential pediatric applications,” he says. He mentions antibody-based therapies as additional promising approaches, including antibody-drug conjugates and “bi-specific” antibodies. Impressive cancer drug trial results have researchers asking: What’s next? Conjugates are monoclonal antibodies—lab proteins that attach to certain targets, such as antigens (foreign substances in the body) on cancer cells—that are chemically linked to drugs. The antibodies release the drugs, which 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 uses them to fight cancer. Experts point out that the technological advances underpinning these therapeutic advances do not fully explain the current resurgence. They praise the work of parent advocacy groups. the willingness of hospitals and academic institutions to…
