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 patients¹ remains unacceptable, and considerable efforts are being made 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 2010.¹ 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).^2–4 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.^5–7 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.^8–11

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.¹² 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 colony-stimulating factor, interleukin-2, and the differentiating agent isotretinoin, or isotretinoin alone in the postconsolidation setting clearly demonstrated improved outcomes as a result of immunotherapy.¹³ 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).¹³

Although GD2-directed immunotherapy is targeted therapy, it is associated with significant toxicity. Patients frequently experience pain, allergic reactions, blood pressure changes, and fevers.¹³ 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.^14–16

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 anti-GD2–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 al¹⁷ 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. NK-mediated cytotoxicity can be reduced by an inhibitory interaction between KIR and HLA ligands.¹⁸ In the absence of this inhibition, GD2-directed immunotherapy may potentially be more effective. Rather than evaluating polymorphisms in either KIR or HLA alone as candidate biomarkers for effectiveness of GD2-directed therapy, of importance, the authors focused instead on the predicted strength of interaction between the protein products of KIR3DL1 andHLA-B genes. The concept of KIR licensing has been previously studied in the transplant setting in which it has been shown that the presence of inhibitory and activating KIR phenotypes and their specific receptors can predict immune response against malignancies.^19,20 Forlenza et al¹⁷ build on this work and on previous studies of KIR and KIR ligand polymorphisms in the setting of neuroblastoma treatment, in particular, regarding response to GD2-directed immunotherapy^21,22 as well as stem cell transplantation.²³ Forlenza et al¹⁷ studied a large cohort of patients (N = 245) who were treated with 3F8 at a single institution and analyzed outcomes with respect to the expected degree of interaction between receptor and ligand. On the basis of KIR3DL1 and HLA-B genotypes, patients were grouped as having potential for no interaction, weak interaction, or strong interaction between the cell-surface receptor and ligand. Patients treated with 3F8 who were categorized as noninteractors as a result of the absence of KIR3DL1 receptor expression, absence of HLA-Bw4 ligand, or failure of interaction of receptor and ligand (n = 127) were shown to have higher OS and PFS rates than did patients who were categorized as strong interactors (n = 63) or weak interactors (n = 55) in both univariable and multivariable analyses. Although the majority of patients who were classified as noninteractors were designated as such because of the HLA-Bw6 genotype rather than the HLA-Bw4genotype, a trend toward higher OS and PFS remained when patients with the Bw6genotype were excluded from the analysis. This lends support to a strategy that focuses on the interaction between receptor and ligand rather than the use of a single marker for prediction of outcome in the setting of anti-GD2 antibody therapy.

The results of this single institution, retrospective analysis are intriguing, but they must be viewed in the context of several limitations. Although the sample size is large, patients were treated over a long period of time (1994 to 2007), and treatment modifications have led to improved survival for patients with high-risk neuroblastoma during this period.¹ Although the multivariable analysis performed included several clinical variables, treatment era was not evaluated. Moreover, the patient population was heterogeneous with respect to prior therapy and disease status. To address the issue of patient heterogeneity, the authors performed a subset analysis that included children who were age > 18 months at diagnosis with International Neuroblastoma Staging System stage 4 disease who had experienced complete or good partial responses after initial therapy. In this somewhat more uniform population (n = 66), OS and PFS remained superior in noninteractors compared with strong interactors. Whether this finding is applicable to the general population of children with high-risk neuroblastoma who were treated with anti-GD2 therapy remains to be seen. It is important to note that the population studied here consisted only of patients who survived long enough and were well enough to travel to the treating institution for 3F8 therapy. A prospective, multicenter trial of uniformly treated patients would be required to definitively determine the validity of noninteractor status as a predictive biomarker in the context of GD2-directed immunotherapy. Finally, the patient population included only those who were treated with 3F8 and, therefore, it is not clear whether interactor status is truly a predictive biomarker for this particular therapy. Others have shown that KIR and HLA genotypes correlate with outcome in the setting of autologous stem cell transplantation,²³ which raises the possibility that interactor status may be prognostic of outcome in high-risk neuroblastoma but not necessarily predictive of benefit from GD2-directed immunotherapy. This question could be readily addressed by assessing interactor status in patients who are treated with and without an anti-GD2 antibody.

Should the above concerns be addressed and interactor status indeed be shown to be a predictive biomarker, this would be an important step forward for the field. Forlenza et al¹⁷ suggest that patients who are categorized as weak or strong interactors may benefit from treatments that could augment NK antibody-dependent cellular cytotoxicity. This approach could certainly be considered; however, it is also possible that if a cohort of children with high-risk neuroblastoma who are highly unlikely to respond to GD2-directed therapy could be identified, these patients could potentially be spared the considerable toxicities that are associated with anti-GD2 antibody therapy. Such patients could receive alternative immunotherapeutics or other targeted treatments in lieu of anti-GD2 immunotherapy. Studies of predictive biomarkers relevant to therapies such as ¹³¹I-MIBG are in progress, and the inclusion of anaplastic lymphoma kinase inhibitors in therapy for patients with tumors that harborALK aberrations is being actively investigated. Should these biomarker-based studies prove fruitful, and should the results of Forlenza et al¹⁷ be confirmed in a prospective study, we may begin to move away from using a high-risk neuroblastoma package deal and toward the development of tailored regimens that are more effective and less toxic.