Phase 1 Study of Dual-Targeting CAR-NK Cells for Adults with Recurrent or Progressive Glioblastoma and High-Grade Glioma Biomarker-Guided Dose Escalation and Expansion with Locoregional Delivery

What this Trial Is About

Researchers are evaluating a first-in-human Phase 1 study to test dual-targeting chimeric antigen receptor natural killer CAR-NK cells delivered locally for adults with recurrent or progressive glioblastoma or other high-grade gliomas. The study aims to address tumor heterogeneity by using CAR-NK cells that recognize two tumor antigens selected from IL13R2, EGFREGFRvIII, and B7-H3 CD276 to reduce the risk of antigen escape. Participants undergo tumor antigen profiling to determine the most suitable dual-target CAR construct for their tumor. The investigational CAR-NK cells are off-the-shelf allogeneic cells genetically modified to express dual-target CARs with a built-in safety switch and potentially an NK-support cytokine module for persistence. These cells are administered locoregionally through a neurosurgically placed catheter or reservoir into the surgical cavity wall or ventricular system to maximize tumor exposure while limiting systemic effects. The study follows a dose-escalation design with up to three dose levels per biomarker-defined cohort, followed by an expansion phase to further assess safety and preliminary activity. Participants may receive repeat infusions at the recommended dose. Tumor antigen profiles categorize participants into one of three groups receiving CAR-NK cells targeting the two highest-priority tumor antigens. Participants will have tumor tissue tested by immunohistochemistry and molecular methods to guide treatment assignment. They will be closely monitored for adverse events including cytokine release syndrome and neurotoxicity. Tumor response will be assessed by MRI using RANO criteria at regular intervals. Safety and activity will be evaluated during the first 28 days and up to 12 months after infusion. Long-term follow-up for gene-modified cell therapy safety will be conducted per guidelines. The total study duration includes active treatment, dose escalation, expansion, and extended monitoring periods.

Dual-Targeting CAR-NK Cells for Recurrent/Progressive Glioblastoma and High-Grade Glioma