Robert C. Seeger, MD (center), in 1991
Cell lines, or populations of identical cells maintained in a laboratory, are fundamental to even the most basic of biomedical research. With a thriving cell line, researchers do not have to rely on precious, and often rare, patient samples.
“You can be doing some research this week, but then you might wait six weeks to get another sample. So with cell lines, if you had the energy, you could crank things out 24/7,” says Robert C. Seeger, MD, who in 1977 established two new neuroblastoma cell lines; only three had existed previously. What started as a way to foster basic research into neuroblastoma, a pediatric cancer of the sympathetic nervous system, would eventually lead to the creation of the first-ever immunotherapy drug (dinutuximab) approved by the Food and Drug Administration (FDA) to treat pediatric cancer.
In fact, few have had as much of an impact on the understanding and treatment of a single disease as Seeger has had on neuroblastoma, which affects roughly 700 children annually in the United States alone. Seeger, who has served as director of the Cancer Research Program in The Saban Research Institute of Children’s Hospital Los Angeles since 1995, has been at the forefront of cancer immunotherapy and genetics for decades. From his contributions to the creation of dinutuximab, to his work on genetically based risk stratification for neuroblastoma patients, to identifying and treating patients with residual neuroblastoma post-treatment, Seeger has changed the game.
Established two new neuroblastoma (NB) cell lines
Linked the presence of excess copies of the oncogene MYCN to outcomes in patients with NB
Discovered molecule GD2 is increased on NB cells, making it a prime target for drug development
Recruited to CHLA
In 1986, Seeger discovered that neuroblastoma cells have increased amounts of a molecule called GD2 on their surface, making it a prime target for drug development. Using the cell lines Seeger developed, Ralph Reisfeld, PhD, of the Scripps Research Institute produced what are called monoclonal antibodies, proteins that specifically bind a single substance, in this case GD2. After further development and a multitude of clinical trials, including one conducted by Seeger here at CHLA, the antibody now known as dinutuximab, was approved by the FDA in March 2015 for treatment of neuroblastoma.
“It’s actually quite interesting to go back in the history of the cell lines and see how they contributed to an FDA-approved product,” observes Seeger, who is also a professor of Pediatrics at the Keck School of Medicine of the University of Southern Czalifornia. “It takes patience. With basic science, you never know where it’s going to go.”
Seeger would go far beyond the basics and delve deep into the genetics of neuroblastoma. In 1985, he and Garrett Brodeur, MD, now at The Children’s Hospital of Philadelphia, linked the presence of excess copies of the gene MYCN, common for neuroblastoma tumors, to patient outcomes. Seeger’s findings were translated into a test now used worldwide as a means of identifying and predicting which patients are at high risk for relapse and prioritizing the management of their care. This marked the first time a cancer gene had ever been related to outcome in patients, either for children or adults.
“This was at the dawn of the cancer gene, the oncogene era,” says Seeger. “It’s hard to believe that was 30 years ago.” Seeger would continue to work on the genetics of neuroblastoma with other CHLA researchers, including Shahab Asgharzadeh, MD, with whom he demonstrated the efficacy of analyzing multiple genes, rather than just one, in risk stratification for neuroblastoma patients.
“We’re now in an era where you have to look at the genetic signature, or fingerprint, of a tumor to most accurately predict how the patient’s going to do,” explains Seeger.
Named director of the Cancer Research Program at The Saban Research Institute
Developed ex vivo purging of NB cells from bone marrow
Cofounded the New Approaches to Neuroblastoma Therapy (NANT) Consortium
Stratifying newly diagnosed neuroblastoma patients according to their level of risk helps physicians coordinate a better, more personalized treatment plan. But what about patients at risk for relapse? Standard treatments can knock down cancers so they are no longer detected by typical scans like bone marrow biopsies, which detect roughly one cancerous cell among 100 normal cells.
But identifying patients with minimal residual disease (MRD) not detectable through standard tests is incredibly important, as nearly 40 percent of patients relapse due to MRD. This was the goal when Seeger teamed with Asgharzadeh, Richard Sposto, PhD, and Cathy Liu in his laboratory, to develop a far more sensitive test for relapse known as NB5, which allows physicians to identify patients with MRD—even those with just one cancer cell per million cells. With funding from the National Cancer Institute and several foundations, Seeger and his laboratory are currently investigating how to improve immunotherapy—treatments that utilize or boost the body’s immune response—for patients with MRD. This work involves researching the tumor microenvironment, which includes the cellular and molecular environment of tumors in the body. Tumor cells will often recruit some of the body’s normal cells to promote a better environment for cancer proliferation and suppression of potential immune responses, which could hamper immunotherapies administered to patients. Understanding the nature of the tumor microenvironment is critical to improving immunotherapy.
“It’s essentially the ‘seed and soil’ idea: If you have really fertile soil, the plants are going to grow well. If you don’t, they’re not going to grow. Cancer is very similar to that,” Seeger explains.
Completed 10 years clinical testing of anti-GD2 antibody
Anti-GD2 antibody (dinutuximab) approved by the FDA
Lifetime Achievement Award from the Pediatric Blood and Marrow Transplant Consortium
In 2000, as part of his effort to expand therapeutic possibilities for neuroblastoma patients, Seeger cofounded the New Approaches to Neuroblastoma Therapy (NANT) Consortium with Katherine Matthay, MD, of the University of California, San Francisco. The Operations Center for the NANT consortium, directed by Araz Marachelian, MD, is here at CHLA. To date, NANT, which takes lab-based research into phase 1 and 2 clinical trials, has treated more than 500 patients with relapsed neuroblastoma using novel therapies targeted to neuroblastoma cells. It has been 38 years since Seeger established those first cell lines, but he shows no signs of slowing down. His laboratory currently receives $1.8 million in direct costs for research from the National Cancer Institute and various foundations to investigate biomarkers and immunotherapy for neuroblastoma.
“With each new therapy, we keep moving closer to our goal of 100 percent survival,” says Seeger.