A Clinical Study of Multi-target Hi-TCR-T Cells in the Treatment of Advanced Hepatocellular Carcinoma

Inclusion criteria: 1. Patients with advanced HCC who are inoperable and unsuitable for local therapy, and whose disease has progressed or cannot tolerate therapy after first - or second-line therapy, and who meet one of the following requirements: 1) have a histological or cytological diagnosis of HCC; 2) According to the National Health Commission's Guidelines for Primary Liver Cancer Diagnosis and Treatment (2024 edition), the clinical diagnosis was HCC; 2. At least one measurable lesion was present according to RECIST1.1 and mRECIST criteria; 3. The expressions of Nectin4, NKG2DL, TROP2, B7H3 and GPC3 in tumor tissues were detected by immunohistochemistry in primary and metastatic specimens or in white paraffin sections of previous pathological pathology (the expression of tumor cells with a target \>10% is considered positive, and at least 2 targets are required to be positive), as well as the expression of FAP in tumor tissues; 4. The patient's T cell quality (pre-experimental) assessment met the criteria: at least 5 times T cell proliferation within 3 days, and at least 10% lentivirus transduction efficiency; 5. ECOG performance status score of 0-2; 6. Child-Pugh score ≤6; 7. Expected survival time of at least 3 months; 8. No contraindications to peripheral blood mononuclear cell (PBMC) collection; 9. Seven days prior to the first treatment with the study drug, organ function levels must meet the following requirements: Hematology: Hemoglobin (Hb) ≥90 g/L; Absolute neutrophil count (ANC) ≥1.5×10⁹/L; Platelet count ≥75×10⁹/L. Blood Biochemistry: Serum albumin ≥28 g/L; Total bilirubin ≤2× upper limit of normal (ULN); Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3× ULN; Alkaline phosphatase (ALP) ≤3× ULN; Creatinine ≤1.5× ULN. Coagulation Function: International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN; Activated partial thromboplastin time (APTT) ≤1.5× ULN. Cardiac Function: Echocardiography confirms normal diastolic function; Left ventricular ejection fraction (LVEF) ≥50%; No severe arrhythmia. Pulmonary and Renal Function: No severe lung or kidney disease; No active pulmonary infection; Blood oxygen saturation ≥92% in room air. 10. Serum pregnancy test results of women of childbearing age must be negative within 7 days before the first use of the study drug; Fertile men or women with the possibility of becoming pregnant must use a highly effective contraceptive method (such as oral contraceptives, intrauterine devices, abstinence or barrier contraception combined with spermicides) throughout the trial and continue contraception for 12 months after the end of treatment; 11. The subjects voluntarily joined the study, signed the informed consent, had good compliance, and cooperated with follow-up. Exclusion criteria: 1. Uncontrollable active infection (excluding HBV and/or HCV infections); 2. active central nervous system disease, or known concomitant brain metastases with significant neurological/psychiatric symptoms assessed by MMSE; 3. Known allergy to 2 or more non-similar foods/drugs, or known allergy to chemotherapy preconditioning drugs (such as cyclophosphamide, fludarabine); 4. Any toxicity caused by previous antitumor therapy before chemotherapy preconditioning has not returned to grade 1 or below (CTCAE version 5.0); 5. Patients who have participated in or are participating in clinical trials of other drugs/therapies within 4 weeks prior to the first administration of the investigational drug; 6. Major surgery had been performed/received within 4 weeks prior to the first administration of the study drug or had not yet recovered from the side effects of the surgery, live vaccination, and radiotherapy within 2 weeks; 7. Patients who are taking systemic hormone therapy for immunosuppressive purposes (dose \>10mg/ day prednisone or other equivalent hormone) and continue to use within 2 weeks prior to treatment; 8. Pregnant or lactating women; 9. A history of other malignancies within the past 5 years, except cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early prostate cancer, and cervical carcinoma in situ; 10. Active inflammatory bowel disease or digestive tract ulcer; 11. HIV antibody or treponema pallidum antibody test results positive; 12. A large amount of pleural fluid or ascites accompanied by clinical symptoms that require symptomatic treatment; 13. A history of active lung disease (pneumonia, obstructive pulmonary disease, asthma) or active pulmonary tuberculosis; 14. suffering from blood system diseases: leukemia, lymph nodes, myelodysplastic syndrome or myeloma; 15. Except vitiligo accidental immune deficiency disease or autoimmune disease; 16. Clinically significant bleeding symptoms or definite bleeding tendency occurred within 3 months before recruitment, such as cough/hemoptysis of 2.5ml or more per day, gastrointestinal bleeding, esophageal varicose veins with bleeding risk, hemorrhagic gastric ulcer or vasculitis. At baseline, if the stool was positive for occult blood, it could be re-examined; if it was still positive, gastroscopy was required; if the gastroscopy indicated severe esophageal and gastric fundus varices, it could not be included in the group (except those who were excluded by gastroscopy within 3 months before enrollment). 17. Have any clinical problems beyond your control, including but not limited to: 1\) Persistent or active (severe) infection; 2) poorly controlled hypertension (persistent blood pressure \>150/90mmHg); 3) Poorly controlled diabetes; 4) Heart disease (Class III/IV congestive heart failure or heart block as defined by the Heart Society of New York); 5) The following conditions occurred within 6 months before the first medication: deep vein thrombosis or pulmonary embolism; Myocardial infarction; Severe or unstable arrhythmia or angina; Percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting; Cerebrovascular accident, transient ischemic attack, cerebral embolism. 18.have obvious genetic diseases; 19. have received a stem cell transplant or an organ transplant; 20.Those who have a history of psychotropic drug abuse and cannot quit or have a history of mental disorders; 21.other severe, acute, or chronic medical conditions or abnormalities in laboratory tests that the investigator determines may increase the risks associated with participation in the study or may interfere with the interpretation of the study results; 22.Patients who were judged by the investigator to have poor compliance or other conditions that made them unfit to participate in the trial.