Anatomy of a Cancer Drug
Madison, Wisconsin - Paul Sondel is reflective and thoughtful as he tries to sum up the last 30 years of research toward an immunotherapy regimen that kills cells of a rare but deadly pediatric cancer.
Thirty years after the research began, the new drug involved in this regimen, dinutuximab, was approved by the U.S. Food and Drug Administration this past spring. The drug is approved for use in pediatric neuroblastoma patients with a high risk of relapse. Neuroblastoma usually begins in the adrenal glands, abdomen, chest or nerve tissue near the spine. There are an estimated 650 new cases of neuroblastoma diagnosed in the U.S. each year.
"Our hope is that the neuroblastoma cure rate is going to improve because of the drug," said Sondel, professor of pediatrics and pediatric cancer researcher. "But we have to follow these children for a longer period of time to see if they are surviving longer."
A large randomized study that began in 2003 showed that after two years, neuroblastoma patients who took dinutuximab after standard treatments including surgery, chemotherapy, radiation therapy and bone marrow transplant had a 66 percent of cancer-free survival compared to 46 percent for those who underwent the standard treatments only. In the prior years, overall long-term survival rates for neuroblastoma were 20 to 30 percent. What preceded this large randomized study was an interesting meeting of the minds designed to tackle neuroblastoma.
Sondel said in the mid-1980’s, he and other cancer researchers in a collaboration called the Children’s Cancer Group (CCG), a consortium of 50 percent of the childhood cancer treatment centers in the U.S. at that time, were intrigued by an antibody made by Scripps Research Institute researcher Ralph Reisfeld. The antibody was designed to stick to neuroblastoma. While it was skilled at finding and sticking to neuroblastoma, the antibody was not able to directly kill the cancer cells.
At the time, Sondel’s research team was helping to lead the development of a white blood cell activator called interleukin 2 (IL2). IL2 activates the body’s natural killer cells. Sondel visited Reisfeld at his lab in La Jolla, Calif., to find out if a "marriage" between the antibody and IL2 was promising for treatment of high-risk neuroblastoma. The Reisfeld/Sondel experiments showed the combination of the two agents worked, in the test tube; the IL2-activated natural killer cells were potent at killing neuroblastoma cells that had been first treated with Reisfeld’s antibody. Dr. Alice Yu, a researcher at the University of California-San Diego, was testing the same antibody in combination with a different white cell activator, a molecule called granulocyte-macrophage colony-stimulating factor (GMCSF). In addition, Dr. NK Cheung of Memorial Sloan Kettering in New York, was testing a different anti-neuroblastoma antibody together with GMCSF, and seeing similar results.
The clinical development and testing of the antibody that was initially developed by Reisfeld and fellow researcher Steve Gillies were slowed, as no pharmaceutical company was interested in supporting its full development. Drs. Yu, Sondel and other researchers turned to the National Cancer Institute (NCI). The NCI agreed to make the antibody and make it available for clinical testing based on the study data at the time.
Sondel and the CCG began working with Reisfeld’s antibody and IL2 in early clinical trials. Dr. Yu then began testing the same antibody in combination with GMCSF, in collaboration with the Pediatric Oncology Group (POG), a separate consortium of 40 percent of the childhood cancer treatment centers in the USA at that time.
Leaders of the CCG and POG recognized their groups were doing similar work. In 1997, they decided to gather members of both groups in Chicago to talk about how best to use Reisfeld’s neuroblastoma-sticking antibody. The two organizations agreed to work together on a combined study and test the antibody with IL2 and GMCSF. The hope was that the treatment would "mop up" remaining cancer cells that were not killed by standard treatment. But the combined study didn’t get off the ground until 2003 because the protocol development and approval process was very complex; antibody production also became an issue during the study.
Six years after the initiation of the clinical trial, statisticians reported that the study had 60 percent of the number of patients needed for the study. "But the statisticians unexpectedly said that the study should stop," Sondel said. "The results showed clear benefit for the immunotherapy regimen, and this benefit seemed very real and not a coincidence."
The trial yielded clear-cut results that the immunotherapy improved survival rates in children with relapsed neuroblastoma. The immunotherapy then was offered to the children in the study’s standard treatment arm, and subsequently to all children entering into this study. The study results were published in the prestigious New England Journal of Medicine.
Based on these very strong clinical results, showing that this treatment appeared to now be "the standard of care" for high-risk neuroblastoma, the NCI made the further development and licensing of the drug available to any company that wanted to take it on and work toward FDA approval. One company, United Therapeutics, agreed to manufacture the antibody, and to make it available for administration with IL2 and GMCSF, the same neuroblastoma cocktail that was published in the New England Journal of Medicine.
With help from the Children’s Oncology Group (COG, the merged consortium that included both the CCG and the POG), United Therapeutics put together all of the clinical data available regarding this drug, named it dinituximab, and submitted the application for approval to the FDA. The FDA was so impressed that the drug received priority review, shortening the review process by four months. As a result, dinutuximab was approved as one of only a few cancer drugs accepted specifically based on testing in children. Sondel said FDA approval was a significant milestone in his more than 35 years of collaborative study on cancer immunotherapy treatment.
"I was very pleased about FDA approval," Sondel said. "Most importantly, it means that this agent will be available to patients with neuroblastoma that may benefit from the therapy. It took a very long time and many people to move from test tube studies to clinical research. All of this shows the principles of science really do work and that teamwork can make things happen."
Date Published: 07/27/2015