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

Summary

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.

Eligibility

Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Conditions5

Interventions3

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