e 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that has the capacity to treat established cancers, is adoptive cell transfer, a method in which lymphocytes are withdrawn from a patient, activated and/or modified in a culture to boost their tumor-fighting ability, and then re-infused in the patient.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 n