Advanced Hepatocellular Carcinoma (HCC), Metastatic Liver Cancer
Conditions
Keywords
HCC, liver cancer, epatocellular carcinoma, GPC3, glypican-3, B7-H3, CD276, CAR-NK, dual-target, NK cell therapy, adoptive cell therapy, cell therapy, immunotherapy, allogeneic
Brief 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.
Detailed description
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.
Interventions
BIOLOGICALEB-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.
DRUGFludarabine
Lymphodepleting chemotherapy given before CAR-NK infusion.
DRUGCyclophosphamide
Lymphodepleting chemotherapy given before CAR-NK infusion.
Sponsors
Beijing Biotech
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Masking is not used because this is an early-phase cell-therapy study in which real-time safety management, product-specific monitoring, and dose-escalation decisions require investigators and treating teams to know the intervention
Intervention model description
Open-label, nonrandomized, biomarker-confirmed, single-arm study with a Phase 1 dose-escalation segment (3+3 design across 3 dose levels) followed by a Phase 2 dose-expansion cohort at the RP2D. All enrolled participants receive lymphodepleting chemotherapy followed by dual-target GPC3/B7-H3 CAR-NK cells. Responses are assessed by RECIST 1.1 and mRECIST for HCC.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 28 Days |
| Incidence, type, and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) | 12 months |
Secondary
| Measure | Time frame |
|---|---|
| response rate (ORR) by RECIST 1.1 and mRECIST | 6 months |
| Disease control rate (DCR) | 6 months |
| Duration of response (DoR) | 12 months |
| Progression-free survival (PFS) | 12 months |
| Overall survival (OS) | 24 months |
Countries
China
Contacts
CONTACTSeni S Lu, Phd
Outcome results
None listed