High-Grade
Gliomas (HGG) are among the deadliest malignant
tumors of central nervous system (CNS) in pediatrics. Despite aggressive
multimodal treatment - including surgical resection,
radiotherapy and
chemotherapy - long-term prognosis of patients remains dismal with a 5-year survival rate less than 20%. Increased understanding of genetic and epigenetic features of pediatric HGGs (pHGGs) revealed important differences with adult
gliomas, which need to be considered in order to identify innovative and more effective therapeutic approaches.
Immunotherapy is based on different techniques aimed to redirect the patient own immune system to fight specifically
cancer cells. In particular, T-lymphocytes can be genetically modified to express chimeric
proteins, known as
chimeric antigen receptors (CARs), targeting selected
tumor-associated
antigens (TAA). Disialoganglioside GD2 (GD-2) and B7-H3 are highly expressed on pHGGs and have been evaluated as possible targets in pediatric clinical trials, in addition to the
antigens common to adult
glioblastoma - such as
interleukin-13 receptor alpha 2 (IL-13α2),
human epidermal growth factor receptor 2 (HER-2) and
erythropoietin-producing human
hepatocellular carcinoma A2
receptor (EphA2). CAR-T
therapy has shown promise in preclinical model of pHGGs but failed to achieve the same success obtained for
hematological malignancies. Several limitations, including the immunosuppressive tumor microenvironment (TME), the heterogeneity in target
antigen expression and the difficulty of accessing the
tumor site, impair the efficacy of T-cells. pHGGs display an immunologically cold TME with poor T-cell infiltration and scarce immune surveillance. The secretion of immunosuppressive
cytokines (TGF-β, IL-10) and the presence of immune-suppressive cells - like tumor-associated macrophages/microglia (TAMs) and myeloid-derived suppressor cells (MDSCs) - limit the effectiveness of immune system to eradicate
tumor cells. Innovative immunotherapeutic strategies are necessary to overcome these hurdles and improve ability of T-cells to eradicate
tumor. In this review we describe the distinguishing features of HGGs of the pediatric population and of their TME, with a focus on the most promising CAR-T
therapies overcoming these hurdles.