Developing New Treatments for Children with Cancer

Cancer is the leading cause of death from disease among children and adolescents in the United States, with approximately 15,000 new cases and 2,000 deaths among those ages 19 and younger each year. Fifty years ago, many childhood cancers were virtually incurable. However, NCI’s investments in research have led to effective treatments for several types of pediatric cancer, including acute lymphoblastic leukemia (ALL) and Hodgkin lymphoma. Today, the 5-year overall survival rate for childhood cancer has increased to more than 80%, together with substantial decreases in overall mortality for children with cancer.

Nevertheless, progress against all cancers that affect children and adolescents is urgently needed, especially against those for which effective treatments do not currently exist, such as diffuse intrinsic pontine glioma (DIPG) and malignant rhabdoid tumor.

Treatment regimens for children and adolescents with cancer are often associated with substantial short-term toxic side effects. In addition, childhood cancer treatments may cause serious health problems for survivors months or years later, including higher risks of heart disease, stroke, infertility, and second cancers. More research is needed to understand these adverse side effects of treatment and how to prevent or mitigate them.

The rarity of childhood cancers—less than 1% of all cancers diagnosed in the United States each year—makes them difficult to study and discourages pharmaceutical companies from developing treatments. Consequently, NCI’s leadership and funding are critically important for continued progress against childhood cancers.

Research Priorities

NCI supports research ranging from the biology of childhood cancer to clinical trials that test new cancer treatments in children and adolescents in clinical trials. Two areas of focus are molecularly targeted therapies and immunotherapies.

Support the Development of Targeted Therapies for Childhood Cancers

Cancers that arise in children and adolescents often differ from those that arise in adults. For example, they generally have fewer genomic alterations than adult cancers. To address this, NCI supports several initiatives to identify the genomic changes that drive childhood cancers, develop new treatments to target those changes, and test the treatments in precision medicine clinical trials.

Infographic. The Pediatric MATCH trial screens 200 to 300 children and adolescents a year to find treatments based on genetic changes in their tumors
  • The NCI–Children’s Oncology Group Pediatric Molecular Analysis for Therapy Choice (NCI–COG Pediatric MATCH) trial aligns with the Precision Medicine Initiative® in oncology. Launched in 2017, this trial will determine whether treating cancers based on their molecular abnormalities, rather than the type of cancer, can be effective. The trial design was based on the NCI-MATCH trial for adult cancers. NCI–COG Pediatric MATCH is open to children and adolescents who have advanced solid tumors that have progressed on standard treatment or for which no agreed upon standard treatment exists. The trial will enroll patients whose tumors have a molecular abnormality that is targeted by one of the approved or investigational therapies that are being used in the trial.
  • The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative has supported a consortium of scientists who are conducting comprehensive molecular analyses to identify the genomic changes that drive several hard-to-treat childhood cancers. The genomic profiling of pediatric acute myeloid leukemia (AML) at initial diagnosis, remission (after treatment), and relapse (recurrence) was recently accomplished because of this initiative. This profiling confirmed that the genomic features of pediatric AML differ from those in adult AML and provided important information to guide future drug development and clinical management of the disease.
  • The Pediatric Preclinical Testing Consortium is testing cancer drugs in preclinical models of pediatric cancers to help prioritize which agents to pursue in human clinical trials. The consortium includes NCI and five academic research institutions. Albert Einstein College of Medicine is studying models of osteosarcoma; Greehey Children’s Cancer Research Institute is studying sarcoma and kidney cancers; Baylor College of Medicine is studying brain cancers; Children’s Hospital of Philadelphia is studying neuroblastoma; and Australia’s Children’s Cancer Institute is studying leukemia.
  • Childhood cancers are often driven by so-called fusion oncogenes, which are formed when parts of two different genes become joined to one another. To date, few treatments have been developed that target the abnormal proteins, or fusion oncoproteins, produced by these genes. Developing therapies against pediatric fusion oncoproteins is a high priority and an effort that will be accelerated through the Cancer Moonshot℠.
  • DIPG, a type of malignant brain stem tumor, is perhaps one of the most devastating cancers diagnosed in children. Most patients die within 2 years of diagnosis. However, NCI-funded researchers at St. Jude Children’s Research Hospital and the Washington University School of Medicine have recently discovered a specific mutation in DIPG tumors that is thought to drive their growth. The mutation affects a cell’s ability to normally modify a protein, called histone 3.3, in chromosomes as a means of controlling gene expression. This finding has led to a clinical trial of the drug panobinostat (Farydak®) in children with DIPG. The trial is being conducted through the Pediatric Brain Tumor Consortium at ten sites across the country, including NCI’s Pediatric Oncology Branch at the NIH Clinical Center. Formed by NCI, the consortium facilitates multicenter studies, research, and data sharing to improve treatment strategies for children with brain cancers.
  • NCI intramural researchers are leading the development of a new targeted therapy approach for children with rare tumors, such as neurofibroma tumors, a disease in which tumors form in nerve tissue and for which there are no FDA-approved drugs. (Read more about this research in the story about Philip Moss of Alabama.)

Advance Immunotherapies for the Treatment of Children with Cancer

Despite the remarkable progress made in immunotherapy against adult cancers, some immunotherapy approaches have yet to be evaluated for the treatment of childhood cancers. With this in mind, NCI will fund research aimed at advancing more immunotherapies for childhood cancers to the clinic.

  • Major progress in treating childhood acute lymphoblastic leukemia (ALL) with genetically modified immune cells called chimeric antigen receptor (CAR) T cells has researchers hopeful that this type of treatment will represent another major approach for children with cancer. FDA approved the first CAR T-cell therapy, tisagenlecleucel (Kymriah) for childhood ALL, in 2017, and NCI is sponsoring nearly a dozen clinical trials of CAR T-cell therapy in pediatric patients with several other types of cancer.
  • In 2017, for the first time, FDA approved several immune checkpoint inhibitors for children with cancer. The checkpoint inhibitor pembrolizumab (Keytruda®) was approved for pediatric (and adult) patients with classical Hodgkin lymphoma that cannot be cured with existing treatments, as well as pediatric (and adult) patients with solid tumors that have specific genetic features. (See the story.) Avelumab (Bavencio®) was approved for patients age 12 or older who have metastatic Merkel cell carcinoma. FDA expanded its approval of ipilimumab (Yervoy®) to include patients age 12 or older who have advanced melanoma. NCI supported much of the preclinical and early clinical research that led to the approval of ipilimumab. The NCI Experimental Therapeutics Program (NExT) supported the early development of pembrolizumab. NCI is also sponsoring early-phase clinical trials of pembrolizumab in children with aggressive brain tumors and ipilimumab in combination with another immune checkpoint inhibitor in pediatric patients with advanced solid tumors or sarcomas.
  • As part of the Cancer Moonshot, NCI is establishing a Pediatric Immunotherapy Discovery and Development Network to establish a collaborative research network to identify and advance research opportunities for translating immunotherapy concepts for children and adolescents with cancer toward clinical applications. As stated in the Developing Precision Immunotherapies section, the goals of the network are to identify new targets for immunotherapies, developing new pediatric immunotherapy treatment approaches, and defining the biological mechanisms by which pediatric tumors evade the immune system.

Improve the Long-Term Quality of Life of Survivors of Childhood Cancer

NCI works to reduce the severity of treatment side effects for childhood cancer and to identify and address the health problems that may develop many years later, called late effects. The Childhood Cancer Survivor Study, funded in part by NCI, has led to a better understanding of the late effects of childhood cancer treatments and strategies to reduce these adverse effects. More than 35,000 survivors have participated in this study. Among the study’s accomplishments was finding that using less cranial radiation to treat acute lymphoblastic leukemia (ALL) improves the cognitive abilities of survivors. (Read about the experience of childhood cancer survivor and pediatric oncologist Greg Aune, M.D., Ph.D., of the University of Texas Health Science Center, San Antonio.)

Stories of Impact

Novel NCI-supported research approaches herald new ways to treat young patients and improve their long-term quality of life.

Improving Outcomes for Patients with NF1

When 9-year-old Philip Moss ran out of treatment options for his neurofibroma tumors in April 2015, his doctors directed his family to NCI. NCI was leading the only treatment trial in the nation for children with tumors caused by neurofibromatosis type 1 (NF1), a genetic disorder in which painful and often disfiguring tumors of the nerves can grow on or under the skin. These tumors are generally benign, but about 10% of people with NF1 will develop a cancerous neurofibroma. There are currently no Food and Drug Administration-approved therapies for NF1.

Using Tandem Transplants to Treat Neuroblastoma

For many years, less than half of children diagnosed with high-risk neuroblastoma, a cancer that starts in immature nerve cells, would be expected to live 5 or more years after diagnosis. Pediatric oncologist and researcher Julie Park has devoted her career to try to change that. In 2016, Julie and her colleagues demonstrated encouraging improvements using a new approach to treat high-risk neuroblastoma in an NCI-sponsored clinical trial that changed the way the disease is treated in the United States. The trial was conducted by the Children’s Oncology Group (COG), part of NCI’s National Clinical Trials Network.

Searching for Less-Toxic Treatments

Advances in cancer treatment mean that, today, more than 4 out of 5 children diagnosed with cancer will survive and remain cancer free for at least 5 years after diagnosis. Many of these children will ultimately be considered cured of their cancer. However, the chances of either developing a life-threatening health problem or dying early as a result of their treatment approaches 60% by age 50. Potential late effects include cardiovascular disease, second cancers, and premature menopause.

Key Takeaways

  • NCI funds cutting-edge initiatives in childhood cancer research, including efforts to develop precision medicine and immunotherapy treatments, as well as efforts to improve the health and well-being of childhood cancer survivors.
  • NCI advances research and facilitates collaboration against childhood cancers, filling an important gap resulting from the substantial challenges in conducting this research.
  • NCI’s efforts help produce more-effective, less-toxic therapies for all childhood cancers so patients not only survive, but thrive.
  • NCI’s longer-term goal is to use all data generated from childhood cancer research to identify children and adolescents at risk of cancer, detect cancer at the earliest stage, or prevent its development altogether.