A Study to Evaluate Safety and Efficacy of Armored CAR-T Cell Injection C-CAR031 in Advanced Hepatocellular Carcinoma

Inclusion Criteria:

* 1.Voluntary participation and able to sign the informed consent form
* 2\. Aged 18 to 75 years at screening
* 3\. Patients with histologically confirmed hepatocellular carcinoma (HCC) who meet the following requirements: a. Barcelona Clinic Liver Cancer Stage B or C (BCLC B/C) b. Child-Pugh score ≤ 6 c. GPC3 is possibly expressed in tumor tissues
* 4\. Patients with relapsed / progressive disease after at least one prior standard systemic therapy for HCC, or ineligible to accept/unable to tolerate the systemic therapies. Standard systemic therapies may include targeted drugs (such as Sorafenib, Lenvatinib, Donafenib, Apatinib), immune checkpoint inhibitors (such as Atezolizumab, Pembrolizumab, Camrelizumab, Sintilimab, Nivolumab, Toripalimab, Tislelizumab) or chemotherapeutic drugs (such as Oxaliplatin and 5-Fu). Subjects in theC-CAR031 plus Lenvatinib group must meet the following criteria: (1)have not received prior Lenvatinib therapy; (2) Progression or intolerance to one prior line of systemic therapy containing both immune checkpoint inhibitors and VEGF/VEGFR- targeted agents. Subjects in the C-CAR031 combination with Regorafenib group must meet the following criteria: (1)have not received prior Regorafenib therapy; (2) Progression or intolerance to one prior line of systemic therapy containing both immune checkpoint inhibitors and VEGF/VEGFR- targeted agents. Subjects in theC-CAR031 plus Durvalumab group must meet the following criteria:(1) Progression or intolerance to one prior line of systemic therapy containing both immune checkpoint inhibitors and VEGF/VEGFR-targeted agents; (2) no prior immune-related toxicity leading to permanent discontinuation of immunotherapy;(3) no history of ≥ Grade 3 immune-related adverse events (irAEs), or any grade immune-related neurological/ocular AEs. (Note: Subjects with ≤ Grade 2 endocrine AEs may enroll if asymptomatic on stable replacement therapy, excluding those: a. requiring non-corticosteroid immunosuppressants, b. experiencing AE recurrence upon immunotherapy rechallenge, c. or using corticosteroids at \>10 mg/day prednisone or equivalent.) (4) All AEs associated with prior immunotherapy must have resolved or returned to pre-treatment levels prior to screening; (5) Body weight more than 30 kg.
* 5\. At least one measurable target lesion (as per RECIST v1.1)
* 6\. WHO/ECOG performance status (PS) score of 0 or 1 point
* 7\. Expected survival ≥ 12 weeks
* 8\. Left ventricular ejection fraction (LVEF) by echocardiography ≥ 45%
* 9\. No active pulmonary infection; no known history of pneumonitis requiring steroids; absence of acute onset or progressive pneumonitis at baseline.
* 10\. Laboratory tests: a. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L b. Lymphocyte count ≥ 0.4 × 109/L c. Platelet count ≥ 60 × 109/L d. Hemoglobin ≥ 80 g/L e. Total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) f. AST and ALT ≤ 5 × ULN g. Serum creatinine ≤ 1.5 × ULN h. Prothrombin time (PT): prolonged PT ≤ 4 s
* 11\. Patients without history of HBV infection, or with HBV DNA \< 2000 IU/mL (or 10000 copies/mL) at screening who agree to receive anti-virus therapies throughout the study according to the guidelines
* 12\. Negative serum or urine pregnancy test results for females of child-bearing age at screening; In addition, they should agree to take effective contraceptive measures throughout the study
* 13\. Patients who agree to abstain from drinking throughout the study

Exclusion Criteria:

* 1\. History of severe allergic or hypersensitivity to DMSO. Subjects with known allergies to the active components of Lenvatinib, Regorafenib, or Durvalumab will be excluded from respective combination treatment groups.
* 2\. History of liver transplantation
* 3\. History of prior cell therapy
* 4\. Tumor volume \> 50% of the liver.
* 5\. portal stem vein tumor thrombus
* 6\. Moderate to severe ascites.
* 7\. Metastases to bones or central nervous system (CNS), or involved CNS diseasesincluding hepatic encephalopathy, epilepsy, cerebrovascular accidents, etc.
* 8\. Receipt of radiotherapy within 6 weeks prior to apheresis
* 9\. Receipt of Local therapy (such as surgery, ablation, and intervention) within 4 weeks prior to apheresis or presence of unhealed wounds before apheresis
* 10\. Receipt of systemic treatment and failure to meet the minimum requirements for wash-out periods before apheresis: a. Immune checkpointinhibitors: 2 weeks; b. Small molecule target therapy: \< 7 days; c. Systemic anti-tumor therapies using experimental anticancer drugs or other Chinese herbal medicines and Chinese patent medicines with unclear mechanisms: 2 weeks; d. Steroids (except inhaled steroids) or other immunomodulators (including interleukins, interferons, and thymosins) of systemic therapeutic dose: 2 weeks; e. Any unresolved toxicity ≥ NCI CTCAE Grade 2 from prior anticancer therapy, except alopecia, vitiligo, and laboratory abnormalities explicitly permitted by the inclusion criteria.
* 11\. Other history of primary cancers, excluding:a. Nonmelanoma skin cancer cured by resection (such as basal cell carcinoma) b. Cured carcinoma in situ (such as cervical cancer, bladder cancer, and breast cancer)
* 12\. Active hepatitis C virus infection (HCV RNA positive)
* 13\. Syphilis infection
* 14\. History of active/immunodeficient diseases (including but not limited to HIV, systemic lupus erythematosus, inflammatory bowel disease, rheumatoid arthritis, myasthenia gravis, Graves' disease, and hypophysitis; excluding: vitiligo or alopecia, hypothyroidism in patients with stable medical conditions after hormone replacement therapy, any chronic skin conditions that need no systemic treatment, and other diseases judged by the investigator to be of no clinical significance)
* 15\. Persistent and active infections (excluding prophylactic anti-infectives)
* 16\. Uncontrolled hypertension, diabetes, arrhythmia, and symptomatic congestive heart failure
* 17\. Dementia or mental state changes supported by obvious clinical evidence
* 18\. Cardiac insufficiency: class III or IV, according to the New York Heart Association (NYHA) functional classifications
* 19\. Unstable heart or lung diseases
* 20\. Obvious bleeding risks or tendencies
* 21\. Females who are pregnant or breastfeeding or expect to be pregnant or breastfeeding during the study
* 22\. Other diseases that may add further risks to the subject or interfere with the study results as judged by the investigators
* 23\. For combination with Lenvatinib, Regorafenib or Durvalumab, the following will be excluded: a. History of renal disease or nephrotic syndrome; b. Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow formulation, or previous intestinal resection that precludes adequate absorption, distribution, metabolism, or excretion of Lenvatinib or Regorafenib; c. History of ≥ Grade 3 bleeding disorder, vasculitis, or significant gastrointestinal bleeding episodes within 28 days prior to screening; d. History of arterial thromboembolic events (ATEs), including myocardial infarction, cerebrovascular accident, or transient ischemic attack within 6 months prior to screening; e. Serious or non-healing wound, active gastrointestinal ulcer, or bone fracture within 28 days prior to screening; f. Use of full-dose anticoagulants or thrombolytics for non-prophylactic purposes within 10 days prior to screening; g. History of deep vein thrombosis, pulmonary embolism, or any other clinically significant thromboembolism within 3 months prior to screening; h. Presence of symptomatic or uncontrolled hypertension.
* 24\. Uncontrolled intermittent severe chronic gastrointestinal disorders associated with diarrhea (excluded from the durvalumab treatment group).