Abstract Outcomes of children and young adults with recurrent or progressive malignant central nervous system tumors (CNS) remain poor. While immune checkpoint inhibitors and antigen-directed cellular therapies, including CAR T-cells, have demonstrated activity in select tumors, their efficacy in CNS tumors has been limited due to low tumor mutational burden, antigen heterogeneity, immune escape, and challenges related to delivery and toxicity. In contrast, natural killer (NK) cells mediate cytotoxicity in a non-antigen dependent manner representing a promising therapeutic strategy for pediatric CNS tumors. We developed an institutional phase I trial evaluating locoregional administration of ex-vivo expanded, universal donor, transforming growth factor-β-imprinted (TGFβi) NK cells in children and young adults with recurrent, progressive, or refractory malignant brain tumors, including patients with non-bulky metastatic disease. TGFβ imprinting during expansion confers resistance to tumor-associated immunosuppression and enhances NK-cell cytotoxicity and cytokine secretion. The study is conducted at Nationwide Children’s Hospital (Ohio, USA) under an FDA-approved IND leveraging established GMP manufacturing infrastructure to generate cryopreserved, off-the-shelf NK cell from carefully selected donors. Eligible patients (≥12 months to ≤ 39 years) undergo weekly infusion of NK cells either directly into the resection cavity or into the ventricular cerebrospinal fluid using an Ommaya reservoir or programmable ventriculoperitoneal shunt, bypassing the blood-brain barrier targeting both local and disseminated disease. Patients receive escalating doses of universal donor TGFβi NK cells using a standard 3 + 3 dose-escalation design, with up to 12 treatment cycles in the absence of dose-limiting toxicity or disease progression. Primary objectives are to determine safety, feasibility, and recommended phase II dose. Secondary and exploratory objectives include assessment of antitumor activity and correlative studies evaluating NK-cell persistence, immune modulation and cerebrospinal fluid biomarkers. Enrollment began in mid-2025 and the study is open to accrual.
Khan et al. (2026) studied this question.