To Explore the Diversity of Intestinal Flora in Patients With Advanced HCC Combin ed With Anti-PD-1 and Targeted Drug Therapy and the Correlation Between Metabolites and Therapeutic Effect

Inclusion Criteria:

• Patients signed informed voluntary enrollment and expected survival of more than 12 weeks;
• Patients with HCC confirmed by histopathology or cytology or clinic are HBV-related HCC;
• No systematic treatment for HCC has been received in the past, excluding local chemotherapy drugs used in TACE/TAI;
• Not suitable for surgical treatment;
• Child-Pugh Class: Grade A or B (≤7 points);
• BCLC stage C;
• ECOG PS≤1;
• At least one measurable lesion (according to RECIST v1.1 requirement, the length of spiral CT of the lesion is ≥10mm or the short diameter of enlarged lymph nodes is ≥15 mm);
• Organ Function Requirements (within 7 days before treatment):

Blood routine examination: WBC (>1.5 *109/L); PLT (>75 *109/L); HB (>90 g/L); no blood transfusion within 14 days before screening, G-CSF drug correction) Liver function tests: ALB (> 29 g/L); TBiL (< 1.5 * ULN); ALT, AST, AKP (< 5 * ULN); INR (< 2.3) or PT (< 6 seconds) exceeding normal control Renal function: Cr < 1.5 ULN or CCr > 50 mL/min

• Patients with active hepatitis B virus (HBV) infection: must receive anti HBV treatment;
• Fertility women should abstinence or use reliable methods of contraception during the observation of curative effect. Serum HCG test must be negative within 7 days before the study treatment, and must be non-lactating. When it comes to abstinence, partners should also have reliable and effective contraception;
• Assessment of patients who are eligible for anti-PD-1 combined with targeted drug therapy;
• Consent to sign informed consent and follow up for a long time.

Exclusion Criteria:

• Known hepatocholangiocarcinoma, sarcomatoid HCC, mixed cell carcinoma and lamellar cell carcinoma; other active malignant tumor except HCC within 5 years or simultaneously;
• Patients with moderate or severe ascites need therapeutic puncture and drainage or Child score > 2 (except those with small amount of ascites without clinical symptoms);
• Patients with a history of gastrointestinal bleeding or risk of bleeding within 6 months before the start of the study, such as severe esophageal varices, locally active gastrointestinal ulcer lesions, and positive persistent fecal occult blood;
• Known hereditary or acquired bleeding or thrombotic tendency, thrombosis or embolism occurred within 6 months before treatment, and aspirin > 325 mg/day was taken within 10 days before treatment;
• It is known that there is a history of severe allergy to any monoclonal antibody or anti-angiogenesis targeted drug;
• Severe infections occurred within 4 weeks before the start of the study, including but not limited to hospitalization due to infections, bacteremia or complications of severe pneumonia;
• Previous treatment with other anti-PD-1 antibodies or other immunotherapy against PD-1/PD-L1;
• Complicated with other hepatitis virus infection or alcoholic liver disease, hereditary metabolic liver disease, autoimmune liver disease and other liver diseases;
• Congenital or acquired immunodeficiency (HIV, or treatment with immunosuppressive agents or systemic hormones within 14 days before treatment (>10mg/d prednisone or other hormones)
• There are cardiopulmonary diseases that can not be well controlled, such as cardiac insufficiency above NYHA II or LVEF < 50% by color Doppler echocardiography, COPD with repeated pulmonary infections.
• Intravenous antibiotics or prophylactic antibiotics were given in the past month. -Receive immunopotentiation therapy, such as thymosin, Ridaxian, etc.
• Other factors that may affect the results of the study or lead to the forced termination of the study, such as alcoholism, drug abuse, other serious diseases (including mental disorders) requiring combined treatment, accompanied by family or social factors, may affect patient safety.