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

Official title

A Phase 1, First-in-Human, Biomarker-Guided, Dose-Escalation and Expansion Study of Locoregional Dual-Targeting CAR-NK Cells Directed Against IL13Rα2, EGFR/EGFRvIII, and/or B7-H3 (CD276) in Adults With Recurrent or Progressive Glioblastoma or High-Grade Glioma

Overview

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.

Detailed description

Rationale: GBM/HGG is molecularly heterogeneous and may evade single-antigen immunotherapy via antigen loss or heterogeneous antigen expression. This study evaluates a dual-target CAR-NK strategy that can recognize two tumor-associated antigens selected from IL13Rα2, EGFR/EGFRvIII, and B7-H3 (CD276). Target assessment and cohort assignment: At screening, archived and/or fresh tumor tissue (from clinically indicated resection or biopsy) will be evaluated by immunohistochemistry (IHC) for IL13Rα2, EGFR, and B7-H3, and by molecular testing (e.g., RT-PCR or NGS) for EGFRvIII when applicable. Participants will be assigned to one of three biomarker-defined cohorts based on the two highest-priority antigens detected above protocol-defined thresholds. An internal review committee may recommend prioritizing one construct for later expansion based on emerging safety/feasibility/activity signals. Investigational product: The investigational products are off-the-shelf allogeneic CAR-NK cells manufactured from a standardized NK-cell source (e.g., iPSC-derived NK cells or a qualified NK master cell bank) and genetically modified to express a tandem (dual-target) CAR. The constructs include a built-in safety switch (e.g., inducible caspase-9) and may include an NK-support cytokine module (e.g., IL-15) to enhance persistence. The exact dual-target construct used for each participant depends on the screening antigen profile.

Route of administration: CAR-NK cells will be delivered locoregionally to the surgical cavity wall and/or into the ventricular system via a neurosurgically placed catheter/reservoir, to maximize exposure at the tumor site while limiting systemic exposure. Dose escalation and expansion: Each biomarker-defined cohort follows a modified 3+3 dose-escalation schema with up to three dose levels (e.g., 1×10\^7, 3×10\^7, and 1×10\^8 CAR-NK cells per infusion). Dose-limiting toxicities (DLTs) will be assessed during the first 28 days after the first infusion. After an RP2D is identified within a cohort, an expansion stage will further characterize safety and preliminary activity and may allow repeat infusions at the RP2D. Follow-up: Participants will be monitored closely for adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Tumor response will be assessed with MRI using RANO criteria at regular intervals. Long-term follow-up for gene-modified cell therapy safety will be conducted per applicable guidance.

Interventions

• Biological Dual-target CAR-NK cells
  Dual-target CAR-NK cells
• Drug Cyclophosphamide
  Cyclophosphamide
• Drug Fludarabine
  Fludarabine
• Device Intracranial catheter/reservoir for locoregional delivery
  Intracranial catheter/reservoir for locoregional delivery

Primary outcome measures

• Incidence of dose-limiting toxicities (DLTs) [Time frame: 28 Days]
• Maximum tolerated dose (MTD) [Time frame: 12 months]

Secondary outcome measures (4)

• Objective response rate (ORR) [Time frame: 12 months]
• Disease control rate (DCR) [Time frame: 6 months]
• Progression-free survival (PFS) [Time frame: 24 months]
• Overall survival (OS) [Time frame: 24 month]

Eligibility criteria

Inclusion criteria

• 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).
• Karnofsky Performance Status (KPS) ≥ 60.
• Adequate organ function (hematologic, renal, hepatic) as defined by protocol laboratory criteria.
• Ability to undergo brain MRI with contrast (unless contraindicated and alternative imaging is permitted).
• Negative pregnancy test for women of childbearing potential; agreement to use effective contraception during study participation and for a protocol-defined period after infusion.
• Ability to understand and willingness to sign informed consent.

Exclusion criteria

• 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).
• Prior gene-modified cellular therapy (e.g., prior CAR-T/CAR-NK) within 6 months, or prior therapy targeting IL13Rα2, EGFR/EGFRvIII, or B7-H3 where residual engineered cells could confound safety assessments.
• Diffuse leptomeningeal disease as the only site of disease, or anatomy that precludes safe catheter placement (unless specifically allowed by protocol).
• Uncontrolled seizures despite optimal medical therapy.
• Clinically significant cardiovascular disease (e.g., recent myocardial infarction, uncontrolled arrhythmia) that would increase risk with lymphodepletion or infusion procedures.
• Pregnant or breastfeeding.
• Any condition that, in the investigator's judgment, would make the participant unsuitable for the study or could interfere with protocol adherence.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Peking University Shenzhen Hospital — Shenzhen

Identifiers

NCT: NCT07480941 · EBNK-GBM-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗