Comparative evidence on the independent contribution of granulocyte-macrophage colony-stimulating factor to anti-GD2 immunotherapy in neuroblastoma: a systematic review and gap analysis.

OBJECTIVE: To assess comparative evidence on the independent contribution of GM-CSF to the efficacy and safety of anti-GD2 immunotherapy in neuroblastoma and to identify evidence gaps. METHODS: This systematic review was conducted in accordance with the PRISMA guidelines in February 2026. MEDLINE (via PubMed), EMBASE, and the Cochrane Library were searched to identify comparative studies evaluating anti-GD2 immunotherapy with and without GM-CSF in patients with neuroblastoma. In addition, the websites of key oncology societies were searched. RESULTS: No study directly compared otherwise equivalent anti-GD2 regimens that differed only in the inclusion of GM-CSF. Two studies met the broader comparative eligibility criterion and provided only indirect regimen-level information. Both evaluated older, non-licensed murine anti-GD2 antibodies (m3F8 and 14.G2a), and neither evaluated GM-CSF with currently licensed anti-GD2 antibodies. In the retrospective study by Cheung et al., survival outcomes differed across treatment eras; however, GM-CSF was co-administered with 13-cis-retinoic acid and treatment groups also differed with respect to prior stem cell transplantation, induction therapy, baseline characteristics, follow-up duration and supportive care. Therefore, the observed survival differences cannot be attributed to GM-CSF. Toxicity comparisons in this study were also limited by differences in toxicity ascertainment across treatment eras. The prospective phase I/Ib study by Frost et al. was primarily designed to evaluate dose finding and toxicity, included very small and heterogeneous treatment groups, and did not isolate GM-CSF as an independent treatment variable. No eligible comparative study was identified for dinutuximab, dinutuximab beta or naxitamab. CONCLUSION: Available comparative evidence is insufficient to determine the independent contribution of GM-CSF to the efficacy or safety of anti-GD2 immunotherapy in neuroblastoma. These findings should not be used to justify modification of licensed product-specific anti-GD2 regimens. A randomized trial holding the anti-GD2 backbone and relevant co-interventions constant is needed to isolate the effect of GM-CSF. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251116911.