This is a draft, ClinicalTrials.gov-style example record for a first-in-human Phase 1 study evaluating locoregional administration of dual-targeting chimeric antigen receptor natural killer (CAR-NK) cells in adults with recurrent or progressive glioblastoma (GBM) or other high-grade glioma (HGG). Participants will undergo tumor antigen profiling for IL13Rα2, EGFR/EGFRvIII, and B7-H3 (CD276). Based on this assessment, each participant will receive the most suitable dual-target CAR construct to reduce antigen-escape risk.
Age 18 to 75 years at the time of consent.
Histologically confirmed glioblastoma (WHO grade 4) or diffuse high-grade glioma (WHO grade 3 or 4) that is recurrent or progressive after standard therapy.
Planned clinically indicated tumor resection or stereotactic biopsy (or availability of adequate archived tumor tissue) to support antigen testing and locoregional catheter placement.
Tumor demonstrates expression of at least two of the following antigens above protocol-defined thresholds: IL13Rα2, EGFR (wild-type) and/or EGFRvIII, B7-H3 (CD276).
Active, uncontrolled infection (including uncontrolled bacterial, viral, or fungal infection).
Known HIV infection with uncontrolled viral load; active hepatitis B or hepatitis C with detectable viral load (unless permitted per protocol).
Clinically significant autoimmune disease requiring systemic immunosuppression within the past 6 months.
Requirement for high-dose systemic corticosteroids (e.g., >4 mg/day dexamethasone equivalent) within 7 days prior to lymphodepletion/infusion (physiologic replacement permitted).
Sequential
Dual-target CAR-NK cells
Biological/VaccineDual-target CAR-NK cells (IL13Rα2/EGFR/EGFRvIII construct): Allogeneic natural killer (NK) cells genetically engineered to express a chimeric antigen receptor (CAR) designed to recognize tumor-associated antigens including IL13Rα2, EGFR, and EGFRvIII. This multi-targeting strategy aims to enhance tumor recognition, reduce antigen escape, and improve cytotoxic activity against heterogeneous tumor cell populations. The engineered CAR-NK cells are administered via locoregional delivery (e.g., intracavitary or through an Ommaya reservoir) to achieve targeted anti-tumor effects while minimizing systemic toxicity.
Cyclophosphamide
DrugAn alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity.
Intracranial catheter/reservoir for locoregional delivery
DeviceA device (e.g., Ommaya reservoir) implanted in the brain to enable direct, repeated administration of CAR-NK cells or other therapies into the tumor site or cerebrospinal fluid, improving local drug delivery and reducing systemic exposure.
Fludarabine
DrugA purine analog chemotherapy used in lymphodepletion prior to CAR-NK cell therapy to enhance the expansion, persistence, and anti-tumor activity of the infused cells.
Incidence of dose-limiting toxicities (DLTs) after CAR-NK infusion (CTCAE v5.0; CRS and ICANS grading).
Determination of recommended phase 2 dose (RP2D)
Determination of recommended phase 2 dose (RP2D) if the maximum tolerated dose (MTD) for each biomarker-defined cohort has been established
Objective response rate (ORR) by RANO criteria (CR+PR)
Disease control rate (DCR) by RANO criteria
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