Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor. We will develop immunotherapy based on the adoptive transfer of natural killer (NK) cells as a candidate approach for the treatment of children with DIPG and other high-grade gliomas. We will leverage our multidisciplinary team and platform technologies using artificial antigen-presenting cells to expand clinical-grade NK cells for application in children with brain tumors. Based on pre-clinical data showing that propagated NK cells have cytolytic activity toward DIPG cell lines and that NK cells can traffic in the brain, we will study the safety of infusing NK cells in the lateral ventricles of DIPG patients. The trial will marry two important, emerging concepts in oncology: immunotherapy and loco-regional delivery of therapeutics. We will draw upon experience with our ongoing Phase I clinical trial to assess feasibility, safety and maximum tolerated dose of ex vivo expanded NK cells infused directly into the fourth ventricle of pediatric patients with tumors of the posterior fossa in the conduct of the proposed trial with DIPG patients. We recently completed infusion of three pediatric brain tumor patients at the first dose level of NK cells without any adverse events attributable to immune cell administration.