Abstract Background Brain cancer is the leading cause of cancer-related deaths in children, with limited treatment options for pediatric high-grade glioma (pHGG). Chimeric Antigen Receptor (CAR) T-cell therapy has shown promise in treating hematological malignancies but remains underexplored in pediatric brain tumors due to challenges such as antigen specificity and tumor penetration. CD70, a TNF receptor family member, is significantly overexpressed in HGG and is associated with poor survival. Our novel 8R-70CAR T cells, which incorporate IL-8 receptor modifications, improve tumor trafficking and anti-tumor efficacy by reshaping the tumor microenvironment (TME) and enhancing immune responses. FDA approval (IND#23881) has been obtained for this pediatric trial (NCT05353530). Hypothesis/Objective We hypothesize that 8R-70CAR T cells will effectively target invasive glioma cells, modulate the immunosuppressive TME, and demonstrate safety and feasibility without dose-limiting toxicities (DLTs) in pediatric pHGG patients. The primary objective is to assess the safety, feasibility, and optimal dosing of 8R-70CAR T cells through a dose-escalation Phase I clinical trial. Method/Approach This Phase I trial will enroll 12 pHGG patients (ages 4–18) and utilize patient-derived 8R-70CAR T cells. The trial endpoints include assessing safety, feasibility, and the maximum tolerated dose (MTD). Comprehensive immune monitoring and correlative studies will evaluate therapy efficacy by analyzing immune cell populations, cytokine profiles, and TME changes pre- and post-treatment. Results Preclinical studies have demonstrated improved CAR T cell trafficking, persistence, and robust antitumor efficacy of 8R-70CAR T cells. Notably, findings from the adult GBM trials (NCT05353530) revealed no DLTs in the first two treated patients, highlighting a promising safety profile for this therapeutic approach. Conclusions This Phase I trial aims to establish the safety and feasibility of 8R-70CAR T cells in pediatric malignant gliomas. Its success could significantly advance CAR T cell therapy for other pediatric cancers, offering new hope to children with these devastating conditions.
Ligon et al. (Fri,) studied this question.