The Beginning of the End of Package Deal Therapy for Patients With High-Risk Neuroblastoma?

Treatment of high-risk neuroblastoma remains one of the major challenges in the field of pediatric oncology. Survival of only one half of newly diagnosed patients remains unacceptable, and considerable efforts are beingmade to use tumor genomics, expression profiling, epigenetic analyses, proteomic studies, and analysis of host factors to better understand this malignancy and to develop more effective therapies. Although much remains to be learned, to date, the improvements that have been made are notable, as 5-year overall survival (OS) rates have increased from 29% for patients diagnosed in the early 1990s to 50% for patients diagnosed between 2005 and 2010. This improvement can be attributed to the development of modern multimodality treatment regimens. Clinical trials in Europe and North America have shown that intensive multiagent induction chemotherapy regimens combined with surgical resection of the primary tumor result in high response rates and improvements in event-free survival (EFS). Children’s Cancer Group, Children’s Oncology Group, German Society of Pediatric Oncology and Hematology, and International Society of Pediatric Oncology European Neuroblastoma Research Network studies have shown that consolidation therapies that consist of high-dose chemotherapy with stem cell rescue result in improved EFS. Current consolidation therapy in North America also includes external beam radiation to the primary tumor bed and sites of persistent metastatic disease; this strategy has resulted in low local recurrence rates. Although intensive induction and consolidation therapy extends EFS in children with high-risk disease, neither European nor North American cooperative group trials that have been published to date have demonstrated improved OS as a direct result of these interventions. In this context, the development of immunotherapy that was designed to address minimal residual disease was a major advancement in the field. Early studies indicated that 3F8, an antibody directed against the cell-surface ganglioside GD2, showed promise in patients with high-risk disease. A landmark randomized Children’s Oncology Group study in which patients were assigned to receive either the anti-GD2 antibody, dinutuximab, which was to be administered in combination with granulocyte-macrophage colonystimulating factor, interleukin-2, and the differentiating agent isotretinoin, or isotretinoin alone in the postconsolidation setting clearly demonstrated improved outcomes as a result of immunotherapy. The trial not only showed that anti-GD2 immunotherapy improves EFS when administered to patients who have not experienced disease progression during initial therapy (2-year EFS, 66% v 46% from the start of postconsolidation therapy) but also results in increased OS (2-year OS, 86% v 75% from this time point). Although GD2-directed immunotherapy is targeted therapy, it is associated with significant toxicity. Patients frequently experience pain, allergic reactions, blood pressure changes, and fevers. Like all other components of current high-risk therapy, GD2-directed immunotherapy has been added to the existing backbone of treatment, extending the total duration of this maximally intensive, multimodality therapy. Whereas our understanding of the genomic landscape and the underlying biology of neuroblastoma has increased tremendously during the past decade, and although neuroblastoma investigators have demonstrated a long-standing commitment to the concept of precision medicine through the use of complex risk assessment systems, the therapeutic strategy for high-risk disease has primarily consisted of adding on blocks of toxic treatment and attempting to ameliorate the accompanying adverse effects. The late effects of current standard postconsolidation therapy, including GD2-directed immunotherapy, have not been entirely elucidated, but it is well known that the totality of multimodality therapy delivered to high-risk patients results in a substantial risk of treatment-related adverse events, including endocrine toxicities, hearing loss, and subsequent malignancies. To date, it has not been possible to determine which patients will benefit most from the various components of high-risk therapy. Currently, there are no reliable biomarkers to indicate which patients will experience better outcomes as a result of augmented consolidation therapy and which patients will benefit most from antiGD2–based postconsolidation therapy. Despite the desire of many clinicians and families to maximize antineuroblastoma activity and to minimize toxicity associated with each portion of high-risk therapy, at present, the backbone of high-risk therapy remains, in many ways, a package deal. In the article that accompanies this editorial, Forlenza et al show that it may be possible to identify groups of patients who are more or less likely to benefit from therapy with a GD2-directed antibody (3F8) on the basis of killer immunoglobulin-like receptor (KIR) and HLA-B genotypes. The effect of GD2-directed antibody therapy is largely mediated through natural killer (NK) –directed antibody-dependent cellular cytotoxicity against tumor cells. NKmediated cytotoxicity can be reduced by an inhibitory interaction between KIR and HLA ligands. In the absence of this inhibition,