In the spring of 2009, Dr. Alice Yu received a phone call from the statisticians monitoring a randomized clinical trial she was leading for children with neuroblastoma . The trial was testing an experimental treatment that stimulates the patient’s immune cells to attack tumor cells, an approach that Dr. Yu had been developing and championing for more than 20 years at the University of California, San Diego Medical Center.
“I knew the phone call was going to be good news or a dead end,” recalled Dr. Yu. The news, it turned out, was good. An interim analysis had shown a clear benefit: 66 percent of patients who received the immunotherapy plus standard treatment were alive and free of the disease 2 years later compared with 46 percent of those who had received standard therapy alone.
Reporting their findings in the September 30 New England Journal of Medicine (NEJM), the researchers concluded that the immunotherapy improved survival in children newly diagnosed with neuroblastoma who were at high risk of developing a recurrence and who responded to initial treatment with standard therapies.
Neuroblastoma is the most common cancer diagnosed during the first year of life. The disease arises in the developing cells of the sympathetic nervous system , often leading to tumors in the neck, chest, or abdomen, along with metastases at the time of diagnosis in high-risk patients. Approximately 700 new cases of neuroblastoma are diagnosed in the United States each year, and nearly half of patients have the high-risk form of the disease, with a likelihood of cure around 30 percent (compared with 50 to 90 percent for patients with intermediate- or low-risk disease).
“This trial was a major landmark for a terrible disease,” said Dr. Yu, who conducted the study of 226 patients with her colleagues in the Children’s Oncology Group (COG). After the interim analysis last year, randomization was stopped and the researchers made the immunotherapy available to all eligible patients.
Testing an Idea
The immunotherapy regimen has gone through many versions since Dr. Yu began testing the concept in the late 1980s. The current treatment uses a monoclonal antibody called ch14.18 , which binds to a lipid called GD2 on the surface of neuroblastoma cells. This approach enables immune cells to attack the cancer.
Children who received the immunotherapy had already responded to initial treatment with chemotherapy, radiation, and stem cell transplantation. To enhance the killing of cancer cells, the researchers gave the antibody with two immune-stimulating agents, the cytokinesGM-CSF and interleukin-2 (IL-2).
“To see the best antitumor effect of the therapy, we wanted to activate as many immune cells that could kill tumor cells as possible,” said co-author Dr. Paul Sondel of the University of Wisconsin, Madison. “The immunotherapy is providing a clear benefit, but it’s not yet the complete answer. Forty percent of patients who are eligible for the therapy are relapsing and dying, so we need to do better.”
To understand why some patients recur within 2 years and others don’t, the researchers are studying the tumors and immune responses of patients, hoping to identify biological markers of response and clues that could make the therapy more effective.
Another challenge is to reduce the side effects of the immunotherapy, such as the pain caused by the antibody and the cytokines. “The side effects are substantial, but we have learned how to manage the pain so that the treatment can be given safely without severe pain,” said Dr. Yu, who noted that less-toxic versions of the immunotherapy are in development.
Persistence and Cooperation Pay Off
The ch14.18 antibody is filled, stoppered, capped, and sealed prior to labeling and distribution to the NCI Cancer Therapy Evaluation Program.
The fact that the ch14.18 antibody remained in development as a neuroblastoma treatment is a testament to the persistence and cooperation of Dr. Yu and her COG colleagues. Twice, the small pharmaceutical company that was producing the antibody for early-stage trials was bought by a bigger company, and the second time the producer stopped making the antibody.
A turning point came in 1996, when Dr. Yu flew to Washington, DC, her luggage packed with x-rays and pathology slides from patients in the early-stage trials. A panel of experts examined this evidence and recommended that NCI support the continued development of the antibody-based immunotherapy.
“I’m very grateful for the committee’s decision, because otherwise this antibody would have died,” said Dr. Yu. When no pharmaceutical company was willing to manufacturer ch14.18 for the phase III COG trial, NCI began to produce the agent for the study.
“So much of the credit for the success of this study goes to researchers like Dr. Alice Yu and Dr. Paul Sondel, who laid the groundwork and showed that the use of cytokines can make the antibody more active when [these are] given together,” said Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program (CTEP).
But the antibody’s history also illustrates the unique role NCI can play in developing more effective treatments for rare diseases such as childhood cancers, he added. NCI supported research from the discovery stage through the phase III study that proved the treatment’s efficacy. NCI then ramped up production of the antibody to have enough for every patient eligible for the therapy, he noted.
The Silver Spring, MD-based United Therapeutics Corp. will take over the manufacturing of ch14.18 and be responsible for obtaining FDA approval for its use in treating high-risk neuroblastoma patients.
25 Years in the Making
Dr. Ralph A. Reisfeld identified GD2 as a potential target for immunotherapy in 1985, and it took nearly 25 years to prove the concept in the clinic. But the researchers point out that the current study could now be a model for testing monoclonal antibodies such as rituximab, trastuzumab, and cetuximab in combination with cytokines as part of therapy for other cancers.
“Based on our results, we think that it might make sense to test these monoclonal antibodies in combination with GM-CSF and IL-2 in the appropriate patients who do not have bulky tumors,” said Dr. Sondel. Most of the responders in the current trial were in remission or had minimal evidence of cancer following the extensive first-line therapy.
“Although it took 25 years to get an answer, neuroblastoma is a rare disease, and it was terrific that we were able to get an answer,” Dr. Sondel noted. He attributed success largely to cooperation among the COG investigators and NCI support and involvement.
Despite the many challenges along the way, Dr. Yu always believed in the approach after seeing patients improve in the early-stage trials. “Some patients in those early trials were supposed to be doomed, and yet they are still alive today,” she said. “A patient from Tennessee came to see me when he was 2 years old, and he is now 22.”
Also in the Journals: Reduced Doses Effective in Lower-risk Neuroblastoma Patients
Substantially lower doses and duration of chemotherapy were as effective as more intensive treatments for neuroblastoma in patients with an intermediate risk of recurrence, researchers reported last week in the New England Journal of Medicine. The patients in the prospective, nonrandomized trial received reduced doses of chemotherapy and no radiation therapy, which had been used in the past. The goal was to determine whether a 3-year estimated overall survival of more than 90 percent could be maintained with reductions in chemotherapy dose and duration and with biologically based treatment assignments.
The average 3-year overall survival of patients in the trial was 96 percent. “We maintained outstanding survival rates for these patients by dramatically reducing the amount of chemotherapy and by eliminating radiation therapy,” said co-author Dr. John Maris of the Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine.
Taken together, this trial and Dr. Yu's trial show that researchers may need to consider the risk levels of patients when developing therapies, according to Dr. Maris. For the intermediate-risk group, the goals were to reduce doses and achieve a cure without toxicity. But for the high-risk patients, the goal was to use more targeted approaches because the standard treatments for this group had already reached the maximum levels of tolerable toxicity for patients.