Current Trends in the Treatment of Children with Neuroblastoma

Abstract

The era of neuroblastoma immunotherapy began with the proof of the effectiveness of monoclonal antibodies to the disialoganglioside GD2, which is expressed on the membrane of tumor cells. Today, these antibodies are included in maintenance therapy regimens for high-risk neuroblastoma. A promising area of immunotherapy for neuroblastoma is the creation of T cells that carry a chimeric antigen receptor to the membrane structures of the tumor (CAR-T cells). Inhibitors of “immunologic checkpoints” – antibodies that block the PD1 receptor and the corresponding PD-L1 ligand – also have theoretical grounds for immunotherapy of neuroblastoma. The introduction of immunotherapy into traditional multicomponent treatment requires further study to optimize the use of this technology for patients with high-risk neuroblastoma. The introduction of multimodality therapy, including surgery, radiation, and aggressive combination chemotherapy, has improved outcomes for many children with high-risk neuroblastoma, but scientists seem to have reached a plateau in what can be achieved with cytotoxic therapy alone. Most children with cancer, including high-risk neuroblastoma, do not benefit from treatment with immune checkpoint inhibitors (ICIs), which have revolutionized the treatment of many highly immunogenic solid tumors in adults. This likely reflects the low mutation rate of the tumor as well as the downregulation of MHC-I that characterizes most high-risk neuroblastomas. For these reasons, neuroblastoma represents an immunotherapeutic challenge that may serve as a model for the development of effective immunotherapy for other cold tumors in children and adults who do not respond to ICI. The identification of strong expression of the disialoganglioside GD2 on the surface of nearly all neuroblastoma cells provided a target for immune recognition by anti-GD2 mAbs, which recruit Fc-receptor-expressing innate immune cells that mediate cytotoxicity or phagocytosis. The adoption of anti-GDNA antibodies in both preliminary and relapse treatment protocols has dramatically improved survival rates and changed the landscape for children with high-risk neuroblastoma. The author set the goal of this work to analyze the latest publications and basic experience on the mechanisms of innate and acquired immunity against neuroblastoma and the use of immunotherapy in its treatment. The work on the article was accompanied by an analysis of the literature over the past seven years. The author notes that neuroblastoma is currently one of the most difficult malignant tumors in children to diagnose and treat, developing from immature nerve cells, neuroblasts. Neuroblastoma can form throughout the sympathetic nervous system. The clinical and biological behavior of this tumor is heterogeneous. It can both progress rapidly with a fatal outcome and spontaneously regress or differentiate into a mature ganglioneuroma (benign tumor). Neuroblastoma is a malignant extracranial solid tumor that is most commonly found in children. In addition, it is the most common solid tumor in young children. The peak incidence of neuroblastoma occurs in children in the first year of life, and 90% of all cases are diagnosed before the age of 10 (most often in children under 5 years). Malignant tumors that develop in childhood are characterized by a relatively low level of genetic instability and, as a result, somatic mutations compared to “adult” tumors. This leads to their lower immunoreactivity and evasion of immunologic surveillance. At the same time, during the development of neuroblastoma, the most common extracranial solid tumor of childhood, the immune system response can unfold quite early. The low mutation rate of the tumor, as well as the downregulation of MHC-I, which characterizes most high-risk neuroblastomas. This phenomenon opens up additional opportunities in planning the treatment of neuroblastoma and gives hope for a good effect of immunotherapy. Despite quite remarkable successes in the treatment of solid tumors in children over the past 20-30 years, due to the widespread use of cytostatic therapy in combination with surgery and radiation treatment, in recent years, scientists and practitioners have reached a so-called “plateau” in the overall survival rate in children with malignant tumors. Unfortunately, neuroblastoma is no exception to this rule. The creation of modern diagnostic and treatment protocols that include various combinations of chemotherapy drugs and staged surgical care has increased the overall survival rate from this pathology to 60–65%. This is a fairly good result, but in the last 7–10 years, this result has not improved, and the effectiveness of treatment of aggressive resistant forms of the tumor still does not exceed 10–15%. For these reasons, neuroblastoma represents an immunotherapeutic challenge that may serve as a model for the development of effective immunotherapy for other “cold” tumors in children and adults who do not respond to ICI.