Researchers at St. Jude Children’s Research Hospital found that adding a novel anti-disialoganglioside GD2 (anti-GD2) monoclonal antibody to the standard therapy for children newly diagnosed with high-risk neuroblastoma significantly enhanced response to treatment and improved survival. Their findings could be transformative if additional studies can produce similar results.
High-risk neuroblastoma claims the lives of about half of patients — most of whom are younger than 5 — within five years, according to the American Society of Clinical Oncology. Treatment is complex, beginning with induction therapy comprised of intensive, multiagent chemotherapy and surgery, followed by consolidation therapy of myeloablative chemotherapy with stem cell rescue and radiation therapy. Finally, patients receive post-consolidation therapy consisting of the anti-GD2 antibody dinutuximab, isotretinoin and granulocyte-macrophage colony-stimulating factor (GM-CSF), according to Wayne Furman, MD, recently retired member of the Department of Oncology at St. Jude.
“Neuroblastoma is a very infiltrative tumor, and often involves multiple major organs and surrounds major blood vessels, making surgical resection very difficult,” Dr. Furman says. “Although about 80% of patients classified as having high-risk disease usually respond to the initial therapy, more than half recur, and when [disease] recurs after this intensive, multimodal therapy, it usually is fatal.”
In a 2010 study, a team led by Alice Yu, MD, PhD, of the University of California, San Diego, demonstrated that post-consolidation immunotherapy featuring dinutuximab, GM-CSF and interleukin-2 (IL-2) markedly improved outcomes compared with standard therapy in high-risk neuroblastoma patients. The FDA approved dinutuximab for these patients in 2015. Meanwhile, Dr. Furman and his colleagues were investigating a novel, GD2-targeting antibody called hu14.18K322A. The novel antibody is owned by biotech company EMD Serono and produced on the St. Jude campus.
“Both [dinutuximab and hu14.18K322A] target a disialoganglioside [GD2] almost universally expressed on the cell surface of neuroblasts,” Dr. Furman says. “Our dose-finding study of hu14.18K322A showed children were able to tolerate more hu14.18K322A than dinutuximab, and we thought that if dinutuximab worked in post-consolidation, what would happen if we used an anti-GD2 antibody throughout therapy?”
Targeting GD2 From the Start
In a prospective, single-arm, three-stage, phase 2 clinical trial, Dr. Furman and his colleagues administered induction chemotherapy and hu14.18K322A, GM-CSF and IL-2 concurrently to 64 patients; 63 were evaluable. For consolidation therapy, patients received the chemotherapy medications busulfan and melphalan — and, when available, patient-derived natural killer T cells with hu14.18K322A — followed by radiation therapy. Post-consolidation treatment consisted of hu14.18K322A, GM-CSF, IL-2 and isotretinoin.
The St. Jude antibody is 98% humanized — dinutuximab, by comparison, is chimeric, containing both humanized and mouse proteins — and engineered to cause less complement-related neuropathic pain than other anti-GD2 antibodies, including dinutuximab. Based on the higher tolerance for hu14.18K322A observed in their dose-finding study, the researchers administered a dose of the novel antibody nearly 2.5 times higher than the maximum tolerable dose of dinutuximab (40 milligrams per square meter for hu14.18K322A compared with 17.5 mg/m2 for dinutuximab). Most patients were able to receive hu14.18K322A infusions in four hours compared with 10 for dinutuximab.
After the first two chemoimmunotherapy cycles, 66% of patients exhibited partial responses or better, a nearly 30-percentage-point improvement compared with the results of a 2019 Children’s Oncology Group (COG) study that used the same induction chemotherapy regimen. Patients in the St. Jude study had a 3-year event-free survival (EFS) rate of 73.7% and an overall survival rate of 86%. The findings appeared in the Journal of Clinical Oncology.
“Our 3-year EFS of nearly 74% are the best outcome results in this difficult-to-treat group of patients with high-risk neuroblastoma, and includes all patients enrolled, not just those that made it to randomization [in the COG study],” Dr. Furman says. “Another intriguing finding of our study is that no patients experienced progressive disease during induction, which occurred in patients somewhere between 7% to 14% in prior studies.”
A Superior Antibody or a More Potent Dosage?
A key question is whether the promising results from the St. Jude study are due to the potential superiority of hu14.18K322A compared with dinutuximab, or whether it was the former’s higher dose that made the difference.
“It is unknown whether hu14.18K322A is a ‘better’ antibody, except [that] it is better tolerated — patients can tolerate more of it, given over a shorter time period, than dinutuximab,” Dr. Furman says. “Thus, a key implication is that these impressive responses could just be due to a dose effect of [our] antibody. Unfortunately, dinutuximab cannot be given at the doses of hu14.18K322A used in this study.”
Dr. Furman points out that a larger, randomized study needs to verify the results of his investigation, and plans are in the works for that sort of effort (see “Planning to Scale Up”). If a sizable study corroborates the St. Jude group’s findings, Dr. Furman says it could change the standard of care for high-risk neuroblastoma patients.