James Sampson

Background:  Neuroblastoma is the most common cancer in infancy and accounts for 15% of pediatric cancer deaths despite there only being 700-800 new cases per year^{1, 2}. It arises from sympathoadrenal cells of neural crest origin and is very heterogeneous. The vast majority of tumors have been shown to have segmental or whole chromosomal alterations, but few recurrent mutations have been identified in pathogenesis³. Tumors are typically stratified by risk factors, including tumor size and mutations, and treated with a combination of chemotherapy, radiotherapy, and surgery accordingly⁴. Immunotherapy has an emerging presence in the treatment landscape, with anti-GD2 monoclonal antibodies becoming increasingly common in high risk refractory cases. However, significant challenges remain in identifying additional targets and overcoming immunosuppression in the tumor microenvironment (TME).

Methods: An online search in the PubMed database was conducted from 2018 forward using the following keywords/phrases: “neuroblastoma”, “neuroblastoma immunotherapy”, “neuroblastoma CAR T-cells”.

Results:  Current immunotherapy approaches to neuroblastoma center around GD2, a cell surface disialoganglioside highly expressed in neuroblastoma tumors. In normal tissues, GD2 expression is restricted to neurons, skin melanocytes, and peripheral nerve tissue, making it an ideal target⁵.  While anti-GD2 monoclonal antibodies have shown efficacy in high risk neuroblastomas, there are significant challenges in developing other treatments. CAR T-cell therapies have been explored, inducing both GD2 and L1-CAM/CD171 targeting CAR T-cells; however, these have shown limited efficacy with the latter also demonstrating off-target side effects⁶. Other modalities being explored include anti-GD2/GD3 cancer vaccines, antibody-drug conjugates, and natural killer T-cell therapies, but have yet to show similar success to anti-GD2 therapy^4,5. Some limitations include an immunosuppressive TME and mesenchymal transition leading to anti-GD2 resistance^5,7. Additionally, it is difficult to identify other targets that are highly specific to neuroblastoma. Some potential targets have been identified, such as TGF-β1, CD161, PD-1, and the NECTIN2-TIGIT axis, with a combination anti-TIGIT/PD-L1 therapy showing promising results in vivo⁸. GPC2, a surface proteoglycan, has also been identified as a potential target, and CAR T-cells have been iteratively engineered to target this antigen with in vivo success⁹.

Conclusions:  Neuroblastoma is the most common cancer in infancy and comes with a relatively poor prognosis in high risk tumors. Immunotherapy has shown to be a viable treatment option with the emergence of anti-GD2 monoclonal antibodies, but challenges still exist in resistance, immunosuppression, and limited targets. Novel developments are already underway to mitigate these challenges, demonstrating a promising future for neuroblastoma immunotherapy.

Works Cited

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2. Neuroblastoma Survival Rates | American Cancer Society [Internet]. www.cancer.org. Available from: https://www.cancer.org/cancer/types/neuroblastoma/detection-diagnosis-staging/survival-rates.html
3. Pugh, T., Morozova, O., Attiyeh, E. et al. The genetic landscape of high-risk neuroblastoma. Nat Genet 45, 279–284 (2013). https://doi.org/10.1038/ng.2529
4. 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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7. Mabe NW, Huang M, Dalton GN, et. al. Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1. Nat Cancer. 2022 Aug;3(8):976-993. doi: 10.1038/s43018-022-00405-x. Epub 2022 Jul 11. PMID: 35817829; PMCID: PMC10071839.
8. Wienke J, Visser LL, Kholosy WM, et. al. Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy. Cancer Cell. 2024 Feb 12;42(2):283-300.e8. doi: 10.1016/j.ccell.2023.12.008. Epub 2024 Jan 4. PMID: 38181797; PMCID: PMC10864003.
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