B010-A Injection for Treating Patients With GPC3 Positive Advanced Hepatocellular Carcinoma

Inclusion Criteria:

• All subjects must meet all of the following criteria to be eligible for enrollment inthis study:

1. Aged 18-75 years, male or female;
2. Subjects with histopathologically or cytologically confirmed advancedhepatocellular carcinoma (HCC) who are ineligible for surgery or local therapy,have progressed or being intolerant to prior standard systemic therapies (systemic therapies include but are not limited to systemic chemotherapy andmolecular targeted therapy), or those who have no effective treatment options atthe time of enrollment as judged by the investigator;
3. Subjects with at least one stable and evaluable intrahepatic or extrahepatictarget lesion (longest diameter of non-nodal lesions ≥ 10 mm, or short axis oflymph node lesions ≥ 15 mm) at enrollment as per RECIST V1.1 criteria;
4. Subjects with GPC3 positive (> grade 2) tumor tissue samples (> 25% tumor cellspositive staining) as tested by immunohistochemistry (IHC);
5. Subjects with Barcelona Clinic Liver Cancer Stage C (BCLC-C) hepatocellularcarcinoma, or subjects with BCLC Stage B hepatocellular carcinoma who are notamenable to local therapy or have progressed after local therapy;
6. Subjects with expected survival > 12 weeks;
7. Subjects with liver cirrhosis of Child-Pugh grade A (5-6 points);
8. Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0or 1;
9. Subjects with inactive hepatitis B (if HBsAg or HBcAb is positive, then HBV-DNAmust be < 20 IU/mL, and HBsAg-positive patients should have been treated withantiviral therapies as per the Guidelines for the Prevention and Treatment ofChronic Hepatitis B (2019 Edition));
10. The largest diameter of intrahepatic tumors is < 10 cm, and the number ofmultiple tumors is < 10 (if pulmonary metastatic lesions are present, the numberof metastatic lesions is < 6);
11. Subjects with a venous access for mononuclear cell collection;
12. Subjects with adequate bone marrow function that allows for lympho-depletingpre-conditioning and without contraindications for the pre-conditioning asassessed by the investigator;
13. Subjects with liver, kidney, respiratory, cardiovascular functions, andcorresponding hematological levels as defined below:
14. Alanine aminotransferase (ALT) ≤ 5.0 × ULN, aspartate aminotransferase (AST) ≤ 5.0 × ULN, and total bilirubin ≤ 2.5 × ULN at screening;
15. Requirements for blood coagulation at screening: prothrombin time (PT)prolongation ≤ 4 s, fibrinogen ≥ 1 g/L, activated partial thromboplastintime (APTT) ≤ 1.5 × ULN;
16. Serum creatinine ≤ 1.5 × ULN or endogenous creatinine clearance > 50 mL/min (Cockcroft-Gault formula) at screening;
17. Pulmonary function at screening: finger oxygen saturation ≥ 95% at screeningand prior to apheresis;
18. Cardiac function at screening: left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiography within 1 month;
19. Subjects with white blood cell count ≥ 3.0×109/L and lymphocyte count ≥ 0.5×109/L at screening (except for those receiving bridging chemotherapy),platelet count ≥ 75×109/L, hemoglobin ≥ 90 g/L, and neutrophil count ≥ 1.5×109/L (this criterion should also be met within 24 hours prior toapheresis).
20. Female subjects of childbearing potential (all women physiologically capable ofbecoming pregnant) must have a negative serum pregnancy test both at screeningand within 14 days prior to the first dose and are willing to use reliablecontraception methods during the study (within 24 months after the first dose ofcell infusion). For male subjects whose partners are women of childbearingpotential, the subjects should have been surgically sterilized or agree to usereliable contraception methods during the study as well as for additional 1 yearafter receiving the last study treatment;
21. Subjects with ability to understand and sign the Informed Consent Form.

Exclusion Criteria:

• Subjects who meet any of the following criteria cannot participate in this study:

1. Having other uncured malignancies (except cervical carcinoma in situ and basalcell carcinoma of skin) within the past 5 years or at present, or hepatocellularcarcinoma with brain metastases;
2. With a history of any of the following cardiovascular diseases within the past 6months: New York Heart Association (NYHA) Grade III or IV heart failure, cardiacangioplasty or stenting, myocardial infarction, unstable angina, or otherclinically significant heart diseases, or poorly controlled high blood pressure (systolic blood pressure > 150 mm Hg, or diastolic blood pressure > 90 mm Hg), orhypotension that requires treatment with vasopressors;
3. With metastases to the central nervous system (CNS) and clinically significantCNS disorders; with prior or clinically significant CNS diseases at screening,such as epilepsy, seizures, paralysis, aphasia, stroke, severe brain injury,dementia, Parkinson's disease, cerebellar disease, brain organic syndrome orpsychiatric disorder;
4. With prior hepatic encephalopathy or at present;
5. With a history of serious lung diseases, including pulmonary embolism, chronicobstructive pulmonary disease, interstitial lung disease and clinicallysignificant abnormal findings in pulmonary function tests;
6. With an active infection (uncontrolled active infections caused by bacteria,viruses, or fungus requiring systemic therapy) at screening, or has anunexplained fever of ≥ 38.0 °C during screening or prior to the first dose;
7. With known active autoimmune diseases requiring immunosuppressive therapy,including biologics;
8. With a history of organ transplantation or awaiting organ transplantation (including liver transplantation);
9. With ≥ 50% of liver replaced by tumor, or with the main portal vein tumorthrombus, or the mesenteric vein/inferior vena cava has been invaded by tumorthrombus;
10. With a co-infection of HBV and HCV viruses or infections caused by more than twoviruses;
11. Positive HCV-RNA, HIV antibody, or syphilis serology, or any other uncontrollableactive infections;
12. Requiring long-term antiplatelet therapy (aspirin > 300 mg/day; clopidogrel > 75mg/day);
13. Have received prior cell-based therapies such as targeted GPC3 therapy, TCR-Ttherapy, CAR-T therapy;
14. With moderate or higher amount of pleural effusion/ascites with clinicalsymptoms, or have undergone drainage of pleural effusion/ascites within the pastmonth (except for those with only small amounts of pleural effusion/ascitesrevealed by imaging examinations but without symptoms);
15. With active bleeding or coagulation test abnormalities, bleeding tendency orundergoing thrombolytic, anticoagulant, or antiplatelet therapy (except thoserequiring heparin due to PICC or deep vein catheterization), or massivebleeding/blood loss (greater than 450 mL) within 28 days;
16. With a history of gastrointestinal bleeding within 3 months or definite tendencyof gastrointestinal bleeding (e.g., known locally active ulcer lesions, fecaloccult blood positive);
17. Having received any of the following treatments:
18. Have received supportive care such as blood transfusion, platelettransfusion, cell growth factors (except recombinant erythropoietin) within 2 weeks prior to apheresis:
19. Have received anti-PD-1/PD-L1 monoclonal antibody treatment within 4 weeksprior to apheresis;
20. Have used any study drug within 4 weeks prior to apheresis, except those whohave failed to respond to the study treatment or have experienced diseaseprogression during study treatment and at least 3 half-lives have passedprior to peripheral blood mononuclear cell collection);
21. Have undergone any surgical treatment, interventional therapy,chemoradiotherapy, ablation, targeted therapy, treatments with invasiveinvestigational medical devices, or are receiving immunomodulatory therapyfor the disease under study within 2 weeks prior to apheresis;
22. With prior use of prednisone at doses ≥ 15 mg /day (or equivalentglucocorticoids) systemically within 2 weeks prior to apheresis, or mayrequire long-term glucocorticoid therapy during study treatment as judged bythe investigator (except those who have recently or are currently usinginhaled or topical glucocorticoids);
23. Have received any Chinese herbal medicine or Chinese patent medicine tocontrol liver cancer within 2 weeks prior to apheresis.
24. With previous allergic reactions to immunotherapy, have received related drugs (such as tocilizumab, cyclophosphamide), or excipients or matrix componentscontained in B010-A for Injection (e.g., albumin, dimethyl sulfoxide, etc.);
25. Toxicities caused by prior treatments have not recovered to CTCAE Grade ≤ 1,except for alopecia and other events judged as tolerable by the investigator;
26. Unable or unwilling to comply with protocol requirements as judged by theinvestigator.