A Study of Metabolically Armed GPC3 CAR-T Cells Injection (Meta10-GPC3) in Patients with Unresectable Recurrent/Metastatic Hepatocellular Carcinoma.

This is an open-label study. This study is indicated for unresectable recurrent/metastatic hepatocellular carcinoma.The selections of dose levels and the number of subjects are based on clinical trials of similar products and the outcomes of our preliminary clinical studies.

1. Main research objectives:

   To evaluate the safety and tolerability of metabolically armed GPC3 CAR-T cells injection (Meta10-GPC3) in patients with unresectable recurrent/metastatic hepatocellular carcinoma.

2. Secondary research objectives:

(1)To evaluate the efficacy of metabolically armed GPC3 CAR-T-cell therapy in unresectable recurrent/metastatic hepatocellular carcinoma.

(2) To assess the in vivo pharmacokinetic (PK) profile, phenotype, and functional activity of infused GPC3 CAR-T cells.

Inclusion Criteria:

• Age >18 years and ≤75 years, male or female.
• Histologically confirmed recurrent or metastatic hepatocellular carcinoma (HCC) that is not amenable to surgical resection.
• At least one measurable target lesion according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
• Tumor tissue must test positive for GPC3 expression by immunohistochemical (IHC), defined as > 25% of tumor cells staining for GPC3 in the pathological specimen. Preferably, the target lesion sample should be used, including freshly obtained tumor tissue or archival tissue samples deemed acceptable by the investigator.
• Expected survival ≥ 12 weeks.
• Child-Pugh class A.
• Eastern Cooperative Oncology Group (ECOG) performance status was 0-1.
• For subjects who are HBsAg or HBcAb positive, HBV-DNA must be < 2 000 IU/mL; HBsAg-positive patients must receive antiviral therapy according to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Edition).
• Adequate venous access for leukapheresis or venous blood collection.
• Hematologic parameters: WBC ≥ 2.5 × 10⁹/L, platelets ≥ 60 × 10⁹/L, Hb ≥ 9.0 g/dL, lymphocytes ≥ 0.4 × 10⁹/L.
• Biochemical parameters: Serum albumin ≥ 30 g/L; Lipase and amylase ≤ 1.5 × ULN; serum creatinine ≤ 1.5 × ULN and estimated creatinine clearance ≥ 40 mL/min; ALT and AST ≤ 5 × ULN; serum total bilirubin ≤ 2.5 × ULN; prothrombin time ≤ 4s longer above normal.
• Women or childbearing potential must have a negative serum pregnancy test within 14 days before CAR-T cell infusion and agree to use effective contraception for 12 months after infusion. Male subjects with partners of childbearing potential must having undergone a vasectomy or agree to use reliable contraception during the study period.
• Ability to understand and sign the informed consent form.

Exclusion Criteria:

• Pregnant or breastfeeding women, or women of childbearing potential who test positive on a pregnancy test during the screening period).
• Active hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection; seropositivity for Human Immunodeficiency (HIV) or syphilis.
• Any uncontrolled active infection, including but not limited to active pulmonary tuberculosis.
• Therapeutic doses of corticosteroids must be discontinued at least 2 weeks prior to Meta10-GPC3 infusion; any immunosuppressive medications must be discontinued at least 4 weeks before signing the informed consent form.
• History of hypersensitivity to immunotherapy or related agents, β-lactam antibiotics, or other severe allergic reactions.
• History or presence of hepatic encephalopathy.
• Clinically significant ascites, defined as ascites detectable on physical examination or requiring therapeutic intervention (excluding ascites detected only by imaging that does not require intervention).
• Imaging showing that HCC occupies ≥ 50 % of normal liver volume, or presence of tumor thrombus in the main portal vein or inferior vena cava.
• Clinically significant central-nervous-system (CNS) disorders (excluding subjects with CNS HCC metastases).
• Active or decompensated cardiac illness (requiring hospitalization or surgical intervention within the past 6 months), or poorly pression ≥ 160/100 mmHg uncontrolled with medication. Stable coronary artery disease or well-controlled hypertension is allowed.
• Active autoimmune disease requiring immunosuppressive therapy.
• Prior organ transplantation or currently on an organ transplant waiting list (including but not limited to liver transplantation).
• Any anti-HCC therapy within 2 weeks prior to leukapheresis or blood collection, including but not limited to surgical resection, interventional therapy, radiotherapy, chemotherapy, or immunotherapy.
• History or concurrent presence of other malignancies, except for the following: surgically removed non-melanoma skin cancer, cured cervical carcinoma in situ, localized prostate cancer, low-stage bladder cancer, ductal carcinoma in situ of the breast, or any malignancy without recurrence or treatment within the past 2 years.
• Other severe medical conditions, including but not limit to: poorly controlled diabetes (post-treatment HbA1c > 7 %), severe cardiac dysfunction (LVEF < 45 %), myocardial infarction, unstable angina, or unstable arrhythmia within 6 months, pulmonary embolism, chronic obstructive pulmonary disease, interstitial lung disease, forced expiratory volume in 1 second (FEV1) < 60 %, gastric ulcer, history of gastrointestinal bleeding, documented bleeding diathesis, uncontrolled thrombotic events, major bleeding, or DVT within 12 months prior to informed consent.
• Active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré syndrome, amyotrophic lateral sclerosis).
• History of QT-interval prolongation or severe cardiac disease.
• Any other condition deemed by the investigator to make the subject unsuitable for participation in the study (e.g., poor compliance).