Abstract
Pediatric central nervous system (CNS) tumors are the most common solid tumors diagnosed in children and are the leading cause of pediatric cancer-related death. Those who do survive are faced with the long-term adverse effects of the current standard of care treatments of chemotherapy, radiation, and surgery. There is a pressing need for novel therapeutic strategies to treat pediatric CNS tumors more effectively while reducing toxicity – one of these novel modalities is chimeric antigen receptor (CAR) T-cell therapy. Currently approved for use in several hematological malignancies, there are promising pre-clinical and early clinical data that suggest CAR-T cells could transform the treatment of pediatric CNS tumors. There are, however, several challenges that must be overcome to develop safe and effective CAR T-cell therapies for CNS tumors. Herein, we detail these challenges, focusing on those unique to pediatric patients including antigen selection, tumor immunogenicity and toxicity. We also discuss our perspective on future avenues for CAR T-cell therapies and potential combinatorial treatment approaches.
Highlights
Pediatric central nervous system (CNS) tumors are the most common solid tumors diagnosed in children [1]
CNS tumors are the leading cause of pediatric cancer-related death, recently surpassing leukemia [1, 4]. Those who survive face lifelong challenges associated with the standard of care (SoC) treatment, which usually consists of surgery, chemotherapy and/or local or craniospinal irradiation
chimeric antigen receptor (CAR) T-cells targeting the epidermal growth factor receptor (EGFR) 806 epitope that is uniquely expressed on the surface of tumor cells can effectively eradicate glioblastoma (GBM) cells while sparing EGFRexpressing human fetal astrocytes [23]
Summary
Pediatric central nervous system (CNS) tumors are the most common solid tumors diagnosed in children [1]. CNS tumors are the leading cause of pediatric cancer-related death, recently surpassing leukemia [1, 4]. Those who survive face lifelong challenges associated with the standard of care (SoC) treatment, which usually consists of surgery, chemotherapy and/or local or craniospinal irradiation. Chemotherapy leaves patients with off-target organ damage and often neurocognitive deficits [5], and radiation causes debilitating damage to the developing brain [6] Given this persistent mortality and morbidity, there is an urgent need for novel therapies that effectively eradicate CNS tumors in children, providing durable remissions while minimizing treatment-related toxicity. We review the major challenges associated with developing CAR T-cell therapies for pediatric CNS tumors and present our perspective on possible avenues for the future development of more effective CAR T-cell and combinatorial immunotherapies
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