4th Generation Chimeric Antigen Receptor T Cells Targeting Glypican-3

Inclusion Criteria:

1. Aged 18 to 75 years, male or female;
2. Patients with advanced hepatocellular carcinoma (HCC) diagnosed by histopathology or cytology who are not suitable for surgery or local treatment, have developed progressive disease or intolerability after standard systemic therapies (including but not limited to systemic chemotherapy, molecular targeted therapy);
3. According to BCLC, the patients are classified into Grade C or Grade B unsuitable for local treatment/progressive disease after local treatment;
4. In tumor tissue samples GPC3 is detected positive by immunohistochemistry (IHC);
5. According to RECIST 1.1, patients have at least one evaluable target lesion, defined as: the longest diameter of non-lymph node lesion ≥ 10 mm, or the shortest diameter of lymph node lesion ≥ 15 mm); hepatic lesions require arterial phase contrast enhancement;
6. Expected survival is \> 12 weeks;
7. Cirrhosis status Child-Pugh score:≤7;
8. ECOG Performance Status score: 0 to 1 point;
9. If the patient is HBsAg positive or HBcAb positive, HBV-DNA should be \<200 IU/ml. HBsAg positive patients must receive antiviral treatment according to the 2015 China Edition of Guideline for Chronic Hepatitis B Prevention and Treatment;
10. Subjects should have adequate organ functions before screening and pre-treatment (at baseline);
11. Have venous accesses for pheresis;
12. Subjects of childbearing age must undergo a serum pregnancy test within 14 days before the initiation of the study and the result must be negative. In addition, they should be willing to use a reliable method of contraception during the trial (within 52 weeks after cell infusion); male subjects whose spouses are women of childbearing age should undergo sterilization surgery or agree to use a reliable method of contraception during the trial;
13. Understand and sign informed consent.

Exclusion Criteria:

1. Pregnant or breast-feeding women;
2. HCV-RNA, HIV antibodies or Syphilis Serological tests are positive;
3. Any uncontrollable active infection, including but not limited to active tuberculosis;
4. Subjects have clinically significant thyroid dysfunction determined by investigator (serum thyroid hormone assays TT4, TT3, FT3, FT4, and serum thyroid stimulating hormone TSH) which is not suitable for entering into the study;
5. Previous or present hepatic encephalopathy;
6. Current clinically significant ascites, which is defined as ascites that are physically positive or require intervention (e.g., puncture or medication) for control (those whose imaging result shows ascites requiring no intervention may be included);
7. Imaging results:≥50% of the liver is replaced by tumor or portal vein main tumor thrombus, or tumor thrombus invasion of mesenteric vein / inferior vena cava;
8. Patients with known active autoimmune diseases which require to be treated with immunosuppressive agents including biological agents;
9. The side effects caused by the previous treatment of the subjects did not return to CTCAE ≤1; except hair loss and other tolerable events determined by investigator;
10. Patients who had received systemic steroids or other immunosuppressive agents within 2 weeks before collection of mononuclear cells, except those who had recently used or are currently using inhaled steroids;
11. Allergic to immunotherapy and related drugs;
12. Subjects have untreated or symptomatic brain metastases;
13. Subjects have central or extensively metastases in lung;
14. Subjects with unstable or active ulcers and gastrointestinal bleeding currently;
15. Patients with a history of organ transplantation or waiting for organ transplantation (including liver transplantation);
16. Subjects who have undergone antitumor therapy within 2 weeks prior to apheresis;
17. Previously received any chimeric antigen receptor-modified T-cells (CAR-T) , TCR T immunotherapy;
18. Subjects who have undergone PD-1/PD-L1 therapy within 3 months prior to screening;
19. Subjects who have undergone major surgery or significant trauma within 4 weeks prior to apheresis, or who are expected to undergo major surgery during the study;
20. There are no other serious diseases that may limit subjects' participation in this trial;
21. Prior to pretreatment and infusion,the subject has a central nervous system disease sign or an abnormal neurological test result with clinical significance;
22. Prior to pretreatment, subjects developed, including but not limited to, new arrhythmias that could not be controlled with drugs, hypotension requiring pressor agent, bacterial, fungal or viral infections that required intravenous antibiotics. Creatinine clearance rate \<50mL/min; The investigator judges that the subject is not suitable for continuing the trial. Subjects who use antibiotics to prevent infection can continue the trials if judged by the investigator;
23. According to the investigators' evaluation, patients are unable or unwilling to comply with the requirements of the study protocol.