More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient population. In 2013 there will be an estimated 11,630 cases of cancer diagnosed in children 14 and younger compared to over 1.6 million cases diagnosed in adults.
According to Crystal L. Mackall, M.D., chief of the National Cancer Institute's Pediatric Oncology Branch, "Progress against childhood cancer represents one of the success stories of modern medicine. Pediatric cancers were uniformly fatal 60 years ago, but today more than 75 percent of children diagnosed with cancer are cured. Still, cancer remains the leading cause of disease-related death in children over one year of age, and the late effects of standard therapies for childhood cancer are substantial." The outcomes for high-risk pediatric patients (those diagnosed at advanced stages of their diseases) remain quite poor.
Mackall notes that there was significant progress made in treating childhood cancers from the 1960s until about 2000, but there has been a plateau in childhood cancer survival rates for the past decade, particularly for those children with solid tumors such as Ewing sarcoma. Of particular concern is the cost to a patient's longer term health due to late effects of therapy, such as another cancer arising due to the toxicity of the initial treatment. Two-thirds of survivors have late effects, with one-third having severe late effects, despite the fact that survival rates still hover around 75 percent.
To address these challenges, researchers have been developing new immunotherapies, either administered alone or used in combination with standard chemotherapy, radiation therapy and/or surgery. When discussing immunotherapy, one approach that has been studied extensively is the use of cancer vaccines. In 2010, the U.S. Food and Drug Administration approved the first vaccine for any type of cancer—Sipuleucel-T (trade named Provenge)—to treat prostate cancer. This treatment prolongs life in prostate cancer but does not induce tumor regression and thus may have less applicability for more aggressive, rapidly growing cancers, such as many childhood cancers. Therefore, many clinicians are looking at whether tumor vaccines administered as pre-emptive or adjuvant therapies (those that follow or are added onto the primary therapy), might be beneficial in more aggressive cancers. This model is particularly relevant to the field of childhood cancers, where remission is often achieved even in the most aggressive diseases.
One type of adjuvant therapy is dendritic cell vaccination, which has been studied in NCI's Pediatric Oncology Branch for patients with high-risk pediatric sarcomas. For this therapy, patients travel to the National Institutes of Health (NCI is part of NIH) clinical center, where lymphocytes are collected, then the patients return home to their local clinics for chemotherapy or radiation, and finally return to NIH after completion of standard therapy for a combination of dendritic cell vaccination plus therapy for reconstitution of their immune system. This therapy has shown dramatic impact on immune reconstitution with higher CD4 (a type of white blood cell, or lymphocyte, that is important in fighting infection) counts and early results suggest improved long-term control of the cancer.
Another, more aggressive immunotherapy that has the capacity to treat established cancers, is adoptive cell transfer, a method in which lymphocytes are withdrawn from a patient, activated and/or modified in a culture to boost their tumor-fighting ability, and then re-infused in the patient. This approach has shown benefit in treating some patients with melanoma. The technique is now being applied to children with acute lymphoblastic leukemia (ALL) in clinical trials at NIH. Although more than 95 percent of children initially diagnosed with ALL achieve remission, a significant number of them relapse. Once they relapse, the prognosis is poor, with ALL accounting for the most number of deaths from cancer in children.
Beyond cell transfer techniques, genetic engineering can be used to reprogram the patient's lymphocytes to recognize and kill any cell that carries a specific target protein on its surface. For pediatric ALL, the CD19 protein has been demonstrated to be an effective target using this approach. Therapies targeting CD19 in pediatric leukemia can be quite potent, and destroy both malignant and healthy B cells. B cells are a type of white blood cell that comprises the immune system. While loss of healthy B cells is not desirable, standard medical practice allows patients to tolerate this side effect without substantial toxicity.
The process of using genetically engineered T cells (another immune system cell) to recognize CD19 has already been demonstrated to be effective in adults with B cell malignancies, but studies in children are only now underway. In April 2013 at the annual meeting of the American Association for Cancer Research, Daniel W. Lee, M.D., assistant clinical investigator in NCI's Pediatric Oncology Branch, and recipient of a fellowship from the non-profit St. Baldrick's Foundation, discussed results from his ongoing clinical trial. This trial demonstrates anti-leukemia effects using lymphocytes engineered to target CD19 in cases of pediatric ALL that are refractory, or resistant to treatment.
Lee's specific approach involves collecting T cells from children, modifying them in the laboratory so that they would attach to CD19 that is expressed by the leukemia cells. The number of modified T cells, called anti-CD19 CAR T cells, was increased nearly 60-fold in the laboratory before they were returned to the patients.
The researchers used this approach in patients whose disease was non-responsive or has returned after standard treatments. Thus far, the approach appears to be similarly tolerable and effective whether or not a person has had a bone marrow transplant, which many children with refractory ALL have previously undergone. This approach differs from one that, until fairly recently, has often been taken in adults, whereby the harvesting and expansion (increase in numbers) of the cells can take months. Pediatric patients are often in the terminal stages of their disease and don't have months to wait. Therefore, Lee and his associates have developed a method that harvests and expands the cells in 11 days. This time differential turns out to be critical and life-saving.
The NCI Pediatric Oncology Branch's outstanding advances in immunotherapy and other fields received special recognition at the 2013 AACR annual meeting via their selection to co-Lead a Stand Up 2 Cancer Pediatric Dream Team directed at "Immunogenomics to Create New Therapies for High-Risk Childhood Cancers." Their participation in this highly competitive arena illustrates the high esteem the pediatric oncology community has for NCI research in this challenging area, per a statement from AACR: "The pediatric oncology research field will continue to benefit from the dedication of expert researchers such as you and your colleagues."
Whatever the next step in immunotherapies for children may be, either in NCI's Pediatric Oncology Branch or by other researchers across the country, it's clear that recent clinical advances have real promise and will be integrated into many treatment modalities in the years to come. Significantly, they also have the potential to inform clinicians of how to better treat adult cancers.
National Cancer Institute's Pediatric Oncology Branch