Update of NK cell therapy in pediatric brain tumors

Brain tumors in children are the leading cause of cancer-related mortality. Despite advances in various treatment modalities, overall survival has remained poor for these malignancies. Immunotherapy has garnered enthusiasm as a new therapeutic paradigm for these tumors, yet the constraints of the blood-brain barrier (BBB), low mutational burden and the immunosuppressive microenvironment have undermined clinical efficacy. The primary objective of this article is to review NK cell pathophysiology and the preclinical studies that have led to its translation into clinical trials for pediatric brain tumors (PBTs). An overview of strategies to reprogram NK cells, enhance their persistence and homing to tumor sites, and mitigate the tumor microenvironment (TME) will be presented. Use of NK cell therapy is now gaining momentum in PBTs due to its inherent tumor-killing mechanisms, which preclude the need for prior sensitization and MHC-dependent antigen recognition. Off-the-shelf sources of NK cells are often favored due to their lower cost, shorter manufacturing time, and quicker access to patients than autologous cells. Improved methods of ex vivo expansion and innovative multiplexed engineering approaches enable delivery of more efficient NK cells, empowered with robust tumor-specific cytotoxicity, longer in vivo persistence and resistance to the impediments of the TME. The development of newer generations of engineered NK cells now ushers in an era of therapeutic optimism for the treatment of brain tumors. Efforts are ongoing to deliver safe and efficacious clinical trials using these novel therapeutics.