Alice Yu, MD, PhD, Receives Lifetime Achievement Award for Advancing Neuroblastoma Treatment
Alice Yu, MD, PhD, a pediatric oncologist and longtime member of Moores Cancer Center, was recently honored with the Lifetime Achievement Award by the Advances in Neuroblastoma Research Association (ANRA), a global organization of neuroblastoma researchers spanning ~77 countries. Presented at ANRA's biennial meeting in Washington, D.C., the award recognizes Yu's groundbreaking work, which has transformed neuroblastoma treatment through the development of anti-GD2 antibody therapy that targets the disialoganglioside GD2.
"This recognition is not the result of a solo effort," said Yu. "I owe it to the concerted efforts of an incredible community, patients, families, colleagues, and collaborators, especially the early support of the University of California, San Diego's General Clinical Research Center (GCRC) and Moores Cancer Center."
Her pioneering journey began in the 1980s at UC San Diego, when neuroblastoma remained one of the most difficult pediatric cancers to treat. "At the time, we were doing everything: chemotherapy, surgery, radiation, bone marrow transplant, and still losing more than 60% of high-risk patients," Yu recalled. Motivated by this frustration, she began collaborating with immunologist Ralph A. Reisfeld, PhD, at Scripps Research. Together with Nissi Varki, MD, and David Cheresh, PhD, then young postdoctoral researchers in Dr. Reisfeld's lab, they tested monoclonal antibodies in mice injected with neuroblastoma tumor cells and identified an antibody that selectively bound to the tumor with minimal impact on normal tissues.
Encouraged by the results, Yu launched a Phase I clinical trial at UC San Diego using the mouse-derived anti-GD2 antibody. Early responses in children with relapsed, treatment-resistant disease were promising; some even achieved complete clearance of tumors from bone marrow metastases.
As monoclonal antibody technology evolved, a collaborator in Boston, Stephen Gillies, PhD, at Damon Biotech Co., helped convert the mouse antibody into a chimeric version, combining mouse and human components to reduce immunogenicity. This novel approach, introduced in 1989 as the first chimeric antibody submitted for an Investigational New Drug (IND), necessitated extensive discussions with the Food and Drug Administration (FDA) to demonstrate its safety. "It took two years to get the IND approved," said Yu, "but it was a valuable learning experience." Phase I study of this chimeric antibody again showed promising results. Remarkably, a few of these patients are now thriving adults in their 30s. Clinicians at approximately ~30 medical centers, conducting a Phase II study, observed similar clinical responses.
Despite compelling early-phase data, scaling up the therapy for broader testing proved difficult. After three biotech companies supported the initial trials, larger pharmaceutical partners declined to pursue Phase III development, citing the rarity of neuroblastoma as a poor commercial prospect. "I was devastated," she said. "Without industry support, it felt like the work might end there."
Instead, Yu turned to the National Institutes of Health (NIH). She presented her data in person, carrying CT scans, MRIs and bone marrow slides in a heavy suitcase to Washington, D.C. The NIH's Decision Network Committee agreed to produce the antibody in large quantities for a national Phase III randomized trial, bridging the gap left by industry.
The trial, conducted through the Children's Oncology Group, would test the antibody in patients randomized to receive either standard care or standard care plus anti-GD2 therapy. However, enrolling patients proved unexpectedly challenging. The antibody caused neuropathic pain requiring narcotic management, something Yu worked closely with the General Clinical Research Center (GCRC) staff and anesthesiologist Mark Wallace, MD, to address. Still, some families, exhausted from their child's earlier treatment, opted out. Others, randomized to the control group, sought the antibody elsewhere, undermining the study's design.
"Accrual was very slow," she admitted. "But we kept going. "After seven years, in March 2009, the trial's Data and Safety Monitoring Board reported a significant finding of the 257 patients enrolled: a 20% improvement in relapse-free survival at two years (46% vs. 66%). The news came just as Yu had planned a long-awaited family trip to the Galápagos. Still, she gave up her ticket to take part in this important conference and help determine whether to stop the randomization and allow all patients to receive anti-GD2 therapy.
"It was worth it," she said. "We finally had clear evidence that the antibody made a difference."
Patients' interest surged after the research team made the results public. Over the following seven years, nearly 1,200 additional patients enrolled in the therapy through an extended-access protocol as the product progressed toward FDA approval. "That's when it became clear, people understood it works," Yu said. Today, dinutuximab, the chimeric anti-GD2 antibody first tested at UC San Diego, is a standard part of treatment for children with newly diagnosed high-risk and relapsed neuroblastoma.
But Yu is not done yet. While the therapy marked a paradigm shift, long-term follow-up revealed a 15% benefit over five years, which was slightly lower than the initial results. "That means we're still losing some patients," she said. "We need to do better."
She proposed combining chemotherapy and immunotherapy to improve treatment outcomes. A randomized study in patients with relapsed disease showed that chemo-immunotherapy was more effective than chemotherapy alone. The Children's Oncology Group is now testing that finding in a frontline setting to improve survival further.
Reflecting on her career, Yu is most proud of bringing a new therapy from concept to clinic, a feat few investigators get to witness firsthand. "It's incredibly gratifying," she said. "But I didn't do it alone. Bringing the therapy to the clinic was a shared achievement built on collaboration. It is a reflection of what we can accomplish together."