Dual-Target GPC3/B7-H3 CAR-NK Cells for Advanced HCC

Официальное название

A Phase 1/2, Open-Label, Dose-Escalation and Dose-Expansion Study of Allogeneic Dual-Target GPC3/B7-H3 (CD276) Chimeric Antigen Receptor Natural Killer Cells in Adults With Unresectable, Relapsed/Refractory, or Metastatic Hepatocellular Carcinoma

Обзор

open-label trial of an allogeneic dual-target CAR-NK product directed against GPC3 and B7-H3 for adults with advanced hepatocellular carcinoma. The design intentionally uses GPC3 as the primary target anchor because GPC3 is the dominant HCC cell-therapy antigen in current clinical development, while adding B7-H3 to reduce antigen escape and to broaden coverage across tumor and tumor-microenvironment compartments. The study first evaluates safety and dose-limiting toxicities, then expands at the recommended phase 2 dose.

Подробное описание

Hepatocellular carcinoma (HCC) remains a high-mortality solid tumor, and many patients progress after or are not candidates for surgery, transplant, locoregional therapy, immune-checkpoint inhibitors, or tyrosine-kinase inhibitors.

Among HCC-associated cell-surface targets, GPC3 has the strongest disease-specific cell-therapy track record and is widely used as the anchor antigen in HCC CAR-T programs. However, not all HCCs express GPC3 uniformly, and loss or low-density expression may contribute to resistance and escape. B7-H3 is an attractive secondary co-target because it is frequently expressed in HCC tumor and stromal/vascular compartments, is associated with immune suppression and aggressive biology, and may complement GPC3 when antigen heterogeneity is present.

The investigational product in this draft is an allogeneic donor-derived peripheral blood NK-cell product genetically engineered to express a dual-target CAR recognizing GPC3 and B7-H3. To keep this example realistic and conservative, the core registration fields below assume a standard dual-target CAR-NK product plus fludarabine/cyclophosphamide lymphodepletion. If the sponsor later prefers an armored platform , those features can be added in a subsequent protocol version or IND-enabling package.

The study is structured as a phase 1/2 single-group trial. Phase 1 uses dose-escalation to determine safety, the recommended phase 2 dose (RP2D), and feasibility. Phase 2 expands at the RP2D to estimate preliminary anti-tumor activity. Participants receive lymphodepleting chemotherapy before CAR-NK infusion, then undergo protocol-defined safety monitoring, serial imaging, and translational assessments including CAR-NK persistence, serum AFP, cytokine profiling, and ctDNA dynamics.

Because B7-H3 can also be detected at low levels in some normal tissues, the trial is intentionally conservative: it uses central biomarker confirmation, stepwise dose escalation, strict liver function eligibility, and close monitoring for infusion reactions, cytokine-release syndrome, immune effector cell-associated neurotoxicity, hepatotoxicity, cytopenias, infection, and any evidence of off-tumor toxicity.

Вмешательства

• Биопрепарат EB-G3B7-NK dual-target CAR-NK cells
  Allogeneic donor-derived NK cells genetically modified to express a dual-target CAR recognizing GPC3 and B7-H3/CD276. Administered intravenously after lymphodepletion.
• Препарат Fludarabine
  Lymphodepleting chemotherapy given before CAR-NK infusion.
• Препарат Cyclophosphamide
  Lymphodepleting chemotherapy given before CAR-NK infusion.

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) [Срок оценки: 28 Days]
• Incidence, type, and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) [Срок оценки: 12 months]

Вторичные конечные точки (5)

• response rate (ORR) by RECIST 1.1 and mRECIST [Срок оценки: 6 months]
• Disease control rate (DCR) [Срок оценки: 6 months]
• Duration of response (DoR) [Срок оценки: 12 months]
• Progression-free survival (PFS) [Срок оценки: 12 months]
• Overall survival (OS) [Срок оценки: 24 months]

Критерии участия

Критерии включения

• Age 18 to 75 years.
• Histologically or cytologically confirmed HCC, or radiologically diagnosed HCC with mandatory tissue confirmation of target expression before enrollment.
• Unresectable, locally advanced, or metastatic HCC not amenable to curative surgery, transplant, or further locoregional therapy; BCLC stage C, or stage B that is not suitable for or has progressed after locoregional therapy.
• Disease progression on, intolerance to, or ineligibility for at least 1 prior standard systemic regimen.
• Central pathology showing GPC3 positivity in >=25% of viable tumor cells by IHC and B7-H3 positivity in >=10% of tumor cells and/or tumor-associated stromal/vascular cells by IHC.
• At least 1 measurable lesion by RECIST 1.1; intrahepatic lesions must be assessable by contrast-enhanced triphasic CT or MRI.
• ECOG performance status 0 to 1.
• Child-Pugh class A or stable Child-Pugh B7 without uncontrolled ascites or recent encephalopathy.
• Estimated life expectancy >=12 weeks.
• Adequate organ function: WBC >=2.5 x 10\^9/L; platelets >=60 x 10\^9/L; hemoglobin >=9 g/dL; serum albumin >=30 g/L; creatinine clearance >=40 mL/min; AST/ALT <=5 x ULN; total bilirubin <=2.5 x ULN; INR/prothrombin time within protocol-defined range.
• If HBsAg positive or anti-HBc positive, HBV DNA must be <200 IU/mL and the participant must be on appropriate antiviral therapy before lymphodepletion. Controlled HCV is allowed if per protocol.
• Negative serum pregnancy test for participants of childbearing potential and agreement to effective contraception.
• Ability to understand and sign informed consent.

Критерии исключения

• Prior gene-modified cellular therapy (for example prior CAR-T, CAR-NK, or TCR-engineered therapy) within the protocol-defined washout period or with unresolved clinically significant toxicity.
• Active, uncontrolled infection, including uncontrolled bacterial, viral, or fungal infection; uncontrolled HIV; active HBV or HCV with uncontrolled viral load; or active tuberculosis.
• Known active CNS metastases or leptomeningeal disease requiring escalating steroids or urgent local intervention.
• Liver transplant or other solid-organ transplant history, or current requirement for chronic immunosuppression.
• Clinically significant ascites requiring frequent drainage, grade >=2 hepatic encephalopathy within 4 weeks, or recent clinically significant variceal/GI bleeding.
• Extensive liver replacement by tumor (for example >=70%) or complete major portal vein/hepatic venous obstruction judged to create excessive treatment risk.
• Major surgery, locoregional therapy, radiotherapy, or systemic anticancer therapy too close to lymphodepletion per protocol-defined washout period.
• Active autoimmune disease requiring systemic immunosuppressive therapy, or chronic systemic corticosteroids above protocol threshold.
• Clinically significant cardiovascular disease (recent myocardial infarction, unstable arrhythmia, uncontrolled heart failure), uncontrolled pulmonary disease, or other serious comorbidity that materially increases study risk.
• Pregnant or breastfeeding.
• Any other active malignancy that is progressing or requires current systemic treatment.
• Any medical or psychiatric condition that, in the investigator's judgment, would compromise safety, protocol compliance, or interpretation of results.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Peking University Shenzhen Hospital — Шэньчжэнь

Идентификаторы

NCT: NCT07500220 · EB-HCC-DUET-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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