Skip to main content
An official website of the United States government

Looking to the Future of Childhood Cancer Research

, by Malcolm A. Smith, M.D., Ph.D.

Malcolm A. Smith, M.D., Ph.D., Associate Branch Chief, Pediatrics, NCI Cancer Therapy Evaluation Program

Challenges to childhood cancer researchers moving forward are to go beyond 90 percent survival for diseases like acute lymphoblastic leukemia (ALL) and to find cures for those cancers for which we still have no effective treatments. Moreover, these goals must be accomplished in ways that allow children with cancer to survive free of long-term side effects, including treatment-related second cancers. 

Two overarching strategies to meet these challenges are precision medicine and immunotherapy.

Precision medicine is used here to describe treatment approaches that are based on the genomic changes that cause the cancer. As an example, the targeted agent imatinib (Gleevec) is given with chemotherapy as part of standard therapy for children with Philadelphia chromosome-positive (Ph+) ALL based on its activity against the BCR-ABL1 fusion gene that causes Ph+ ALL.

Clinical trials following the precision medicine principle are ongoing for some childhood cancers, including:

  • A high proportion of low-grade gliomas in children have genomic changes that lead to activation of the MAP kinase pathway. An inhibitor of this pathway (selumetinib) is in phase II evaluation for children with low-grade glioma.
  • Most children with anaplastic large cell lymphoma (ALCL) have genomic changes in the ALK gene. An ongoing clinical trial is combining the ALK inhibitor crizotinib (Xalkori) with standard chemotherapy for children with ALCL.
  • Approximately 10 percent of children with acute myeloid leukemia have genomic changes in the FLT3 gene. An ongoing clinical trial is adding a drug that inhibits FLT3, sorafenib (Nexavar), to standard chemotherapy for these children.
  • NCI is also planning a clinical trial called Pediatric MATCH for children with solid tumors that have returned after prior treatment. Samples from patients’ tumors will be sequenced for specific gene mutations, and if a mutation is present that matches the activity profile of one of the targeted agents available through the MATCH trial, the patient will receive this agent.

A number of childhood leukemias and sarcomas result from gene fusions that produce cancer-causing proteins that are not targetable with current anticancer agents. These leukemias (e.g., MLL gene-fusion leukemias) and sarcomas (e.g., Ewing sarcoma, synovial sarcoma, and alveolar rhabdomyosarcoma) show very few other genomic changes. If the precision medicine concept is to have a major impact for children with these cancers, researchers will need to discover ways to target the fusion-gene products.

Immunotherapy has undergone a remarkable renaissance in the past decade, with a number of strategies showing substantial clinical efficacy. The primary immunotherapy approaches are those that focus on antibodies and those that focus on T cells, and both are being pursued for children with cancer.

  • One antibody approach is illustrated by the recent FDA approval for children with high-risk neuroblastoma of a monoclonal antibody targeting the GD2 molecule that is highly expressed on the surface of neuroblastoma cells.
  • Antibody-drug conjugates are antibodies that have highly toxic chemotherapy agents attached to them. The antibody-drug conjugate brentuximab vedotin (Adcetris) targets a protein present at the cell surface on Hodgkin lymphoma and ALCL, and it induces high response rates for each. Clinical trials of brentuximab vedotin are ongoing for children with newly diagnosed Hodgkin lymphoma and ALCL.
  • Bispecific T-cell engaging (BiTE) antibodies have one end that binds to a cancer cell and the other end that binds to a T cell. Bringing the T cell in close proximity to the cancer cell allows the T cell to kill the cancer cell. Blinatumomab (Blincyto) is a BiTE antibody that targets ALL cells, and a pediatric clinical trial is evaluating blinatumomab in children with ALL at first relapse.
  • Chimeric antigen receptor (CAR) T cells are engineered to target cytotoxic T cells to cancer cells. CAR T cells targeting the CD19 antigen present on ALL cells have shown high levels of activity for children and adults with relapsed ALL. A high-priority research area is developing effective CAR T cells for pediatric solid tumors. 
  • Checkpoint inhibitors are antibodies that block a mechanism (i.e., “checkpoints”) that tumors use to evade the immune system. Checkpoint inhibitor antibodies targeting CTLA-4 and PD-1 on T cells (or PD-L1 on tumor cells) have shown activity against a range of adult cancers, including non-small cell lung cancer, renal cell carcinoma, and melanoma. These antibodies are in pediatric clinical trials to learn whether childhood cancers respond to checkpoint inhibitors.

The new treatments described above will hopefully improve survival for some types of childhood cancers. In introducing these agents into curative regimens for children with cancer, it will be essential to monitor for their long-term effects, since new classes of targeted agents will almost certainly have short-term and long-term toxicities.

That said, the components of current standard therapy that lead to long-term side effects (e.g., second cancers, neurocognitive deficits, cardiac toxicity, impaired fertility, hearing loss, etc.) are well known. An important goal in introducing the new classes of agents described above into pediatric treatment regimens is to reduce the harmful components of current treatments while maintaining or improving survival rates. In this way, the objective of achieving cure with high quality of survivorship can be achieved.

A final point is that future progress is more than ever contingent upon collaboration across a large number of children’s cancer centers. Clinical trials for new treatments are now being restricted to smaller and smaller genomically-defined populations. A strong national clinical research program to conduct these clinical trials is essential for efficiently and expeditiously determining whether promising, novel treatments are truly effective.

Malcom A. Smith, M.D., Ph.D. 
Associate Branch Chief, Pediatrics
NCI Cancer Therapy Evaluation Program

This is the first in a series of posts authored by NCI cancer research leaders, inspired by topics covered in the documentary film, Cancer: The Emperor of All Maladies, airing this week on PBS nationwide.

< Older Post

A Week of Excitement and Hope: Communicating the Story of Cancer

Newer Post >

A Message to the Cancer Research Community

If you would like to reproduce some or all of this content, see Reuse of NCI Information for guidance about copyright and permissions. In the case of permitted digital reproduction, please credit the National Cancer Institute as the source and link to the original NCI product using the original product's title; e.g., “Looking to the Future of Childhood Cancer Research was originally published by the National Cancer Institute.”