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  • Review Article
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Advancing therapy for neuroblastoma

Nature Reviews Clinical Oncology volume 19, pages 515–533 (2022)Cite this article

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Abstract

Neuroblastomas are tumours of sympathetic origin, with a heterogeneous clinical course ranging from localized or spontaneously regressing to widely metastatic disease. Neuroblastomas recapitulate many of the features of sympathoadrenal development, which have been directly targeted to improve the survival outcomes in patients with high-risk disease. Over the past few decades, improvements in the 5-year survival of patients with metastatic neuroblastomas, from <20% to >50%, have resulted from clinical trials incorporating high-dose chemotherapy with autologous stem cell transplantation, differentiating agents and immunotherapy with anti-GD2 monoclonal antibodies. The next generation of trials are designed to improve the initial response rates in patients with high-risk neuroblastomas via the addition of immunotherapies, targeted therapies (such as ALK inhibitors) and radiopharmaceuticals to standard induction regimens. Other trials are focused on testing precision medicine strategies for patients with relapsed and/or refractory disease, enhancing the antitumour immune response and improving the effectiveness of maintenance regimens, in order to prolong disease remission. In this Review, we describe advances in delineating the pathogenesis of neuroblastoma and in identifying the drivers of high-risk disease. We then discuss how this knowledge has informed improvements in risk stratification, risk-adapted therapy and the development of novel therapies.

Key points

  • Neuroblastomas are a biologically and clinically heterogeneous group of tumours; this diversity has implications for pathogenesis, prognosis and treatment.

  • Neuroblastomas emerge from cells of the developing sympathetic nervous system and maintain several of the key features of sympathoadrenal tissues, leading to the development of targeted small molecules, radiopharmaceuticals and immunotherapies.

  • Prospective studies of risk stratification and risk-adapted therapy have sustained the excellent outcomes in patients with low-risk and intermediate-risk neuroblastoma while also reducing the incidence of adverse events; improved outcomes have also been achieved in those with high-risk disease.

  • Rational combination strategies will be necessary to further advance therapies for patients with high-risk neuroblastoma, including efforts to increase the response rates to first-line therapies, develop effective salvage therapies for relapsed and/or refractory disease, and sustain disease remissions.

  • High-risk neuroblastomas are able to suppress antitumour immunity via several mechanisms; chimeric antigen receptor engineering and combination strategies designed to enhance antitumour immune function might ultimately overcome these effects.

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Fig. 1: Sympathoadrenal development and neuroblastoma tumorigenesis.
Fig. 2: Immune evasion mechanisms and immunotherapy strategies in patients with neuroblastomas.
Fig. 3: COG version 2 risk stratification schema.
Fig. 4: Multimodal therapy for high-risk neuroblastoma.
Fig. 5: Rational combination strategies targeting neuroblastomas.

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  1. Department of Paediatrics, Division of Paediatric Hematology and Oncology, University of California San Francisco, San Francisco, CA, USA

    Bo Qiu & Katherine K. Matthay

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K.K.M. is a consultant for Illumina Radiopharmaceuticals. B.Q. declares no competing interests.

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Qiu, B., Matthay, K.K. Advancing therapy for neuroblastoma. Nat Rev Clin Oncol 19, 515–533 (2022). https://doi.org/10.1038/s41571-022-00643-z

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