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

Официальное название

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

Обзор

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.

Подробное описание

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 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.

Вмешательства

• Биопрепарат Dual-target CAR-NK cells
  Dual-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., intr
• Препарат Cyclophosphamide
  An alkylating chemotherapy agent used as part of lymphodepleting conditioning prior to CAR-NK cell infusion to enhance cell expansion, persistence, and anti-tumor activity.
• Устройство Intracranial catheter/reservoir for locoregional delivery
  A 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.
• Препарат Fludarabine
  A 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.

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) after CAR-NK infusion (CTCAE v5.0; CRS and ICANS grading). [Срок оценки: 28 Days]
• Determination of recommended phase 2 dose (RP2D) [Срок оценки: 12 months]

Вторичные конечные точки (2)

• Objective response rate (ORR) by RANO criteria (CR+PR) [Срок оценки: 12 months]
• Disease control rate (DCR) by RANO criteria [Срок оценки: 6 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University Shenzhen Hospital — Шэньчжэнь

Идентификаторы

NCT: NCT07551336 · EBNK-GBM-112

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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