This is a single arm and open-label phase I trial to evaluate the safety, tolerability and efficacy of the oncolytic virus M1 （M1-c6v1）(iv 1×109 CCIC50, 1 dose per day, on day 1-5 each 28 day cycle) combined with anti-PD-1 antibody SHR-1201 (iv, 200 mg, once every two weeks) and Apatinib (po. 250 mg qd ) in the patients with advanced/metastatic hepatocellular carcinoma. 10 participants will be sequentially enrolled. The treatment duration is 12 months. All patients continue combination treatment until disease progression, unacceptable toxicity, death, or discontinuation for any reason.

Inclusion Criteria:

1. Aged 18-65 years old, both genders.

2. To be confirmed to meet the clinical diagnosis standard, histologically or cytologically confirmed with hepatocellular carcinoma

3. Life expectancy of at least 3 months.

4. Patients was not received any systemic therapies to HCC.

5. For patients with advanced hepatocellular carcinoma, liver function status Child-Pugh Class A or B (score<=7).

6. HCC staging is evaluated according to Diagnostic and therapeutic criteria for liver cancer (2019 Edition, National health commission, P.R.A)

   • a: with vascular invasion and no extrahepatic metastasis, no matter the tumor condition; Child-Pugh A/B；PS 0~2.
   • b: with extrahepatic metastasis, no matter the tumor condition and vascular invasion; Child-Pugh A/B；PS 0~2, not eligible for surgical and/or locoregional therapies.

7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 2.

8. Patients must have at least 1 lesion that is measurable using RECIST v1.1 criteria (The long diameter of the lesion on spiral CT scan was more than or equal to 10 mm or the short diameter of enlarged lymph node was more than or equal to 15 mm).

9. Patients must have adequate organ function (without blood transfusion, without growth factor or blood components support within 14 days before enrollment)as determined by:

   ① Blood system: Hemoglobin ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥1.5×109/L; Platelet count ≥ 75×109/L.

   ② Liver function: Serum total bilirubin (TBIL)≤2 times the upper limit of normal (ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5×upper limit of normal(ULN), Serum albumin ≥ 28 g/L; Alkaline phosphatase(ALP) ≤5×ULN;

   ③ Kidney function: Calculated creatinine clearance (CrCl) > 50 mL/min (Cockcroft-Gault formula will be used to calculate CrCl); Creatinine (Cr) ≤ 1.5×ULN; Urine protein <2+ or Baseline of urine protein ≥ 2+ and 24h urinary protein quantity ≤ 1g.

   ④ Coagulation function: International Normalized Ratio (INR) or Activated partial thromboplastin time (APTT) ≤ 1.5×ULN

10. Reproductive subjects (male and female) must agree to use effective birth control measures with their partners for at least 180 days after the last medication.

11. Volunteer to participate in clinical research; fully understand and be able to sign the informed consent form (ICF); willing to follow and have the ability to complete all trial procedures.

Exclusion Criteria:

1. Patients must not have had prior treatment with SHR-1210 or any other PD-L1 or PD-1 antagonists or any other oncolytic virus, and must not have had be enrolled in the phase III Study of Apatinib After Systemic Therapy in Patients With Hepatocellular Carcinoma.
2. Patients with any active autoimmune disease or history of autoimmune disease, including but not limited to the following: hepatitis, pneumonitis, uveitis, colitis (inflammatory bowel disease), hypophysitis, vasculitis, nephritis, hyperthyroidism, and hypothyroidism, except for subjects with vitiligo or resolved childhood asthma/atopy. Asthma that requires intermittent use of bronchodilators or other medical intervention should also be excluded.
3. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids. Doses > 10 mg/day prednisone or equivalent are prohibited within 2 weeks before study drug administration. Note: corticosteroids used for the purpose of IV contrast allergy prophylaxis are allowed.
4. Known history of hypersensitivity to any components of the SHR-1210 formulation, or M1-c6v1 (mannitol, human albumin, trehalose).
5. Active central nervous system (CNS) metastases with clinical symptoms (including cerebral edema, steroid requirement, or progressive disease). Subjects with brain or meningeal metastases that were previously treated must be clinically stable (magnetic resonance imaging [MRI] at least 4 weeks apart do not show evidence of new or enlarging metastases) and have discontinued immunosuppressive doses of systemic steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks before study drug administration.
6. Patients with other malignant tumor (except cured skin basal cell carcinoma and cervical carcinoma).
7. Clinically significant cardiovascular and cerebrovascular diseases, including but not limited to severe acute myocardial infarction within 6 months before enrollment, unstable or severe angina, or coronary artery bypass surgery, Congestive heart failure (New York heart association (NYHA) class > 2), ventricular arrhythmia which need medical intervention, left ventricular ejection fraction(LVEF) < 50%.
8. Hypertension and unable to be controlled within normal level following treatment of anti-hypertension agents(within 3 months): systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg.
9. Coagulation abnormalities (PT>16s、APTT>43s、TT>21s、Fbg<2g/L), with bleeding tendency or are receiving thrombolytic or anticoagulant therapy.
10. Prior systemic chemotherapy, radiotherapy, immunotherapy, hormone therapy, surgery or target therapy within 4 weeks (Or 5 half-life of the drug, calculate the longer ) before the study drug administration, or any unresolved AEs > Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 (with the exception of any stable chronic toxicities not expected to resolve).
11. Patients with clinical symptoms of ascites or pleural effusion, need therapeutic puncture and drainage.
12. Previous digestive tract bleeding history within 3 months or evident gastrointestinal bleeding tendency, such as: esophageal varices, local active ulcerative lesions, gastric ulcer and duodenal ulcer, the ulcerous colitis, gastrointestinal diseases such as portal hypertension or resection of tumor with bleeding risk, etc.
13. Patients with or previous with serious hemorrhage (bleeding > 30 ml within 3 months), haemoptysis (> 5 ml within 4 weeks) of thromboembolic events within 12 months (including stroke events and/or transient ischemic attack).
14. Active infection or an unexplained fever > 38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, subjects with tumor fever may be enrolled).
15. Objective evidence of previous or current pulmonary fibrosis history, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, pulmonary function damaged seriously etc.
16. History of immunodeficiency including seropositivity for human immunodeficiency virus (HIV), or other acquired or congenital immune-deficient disease, or active hepatitis (transaminase does not meet the inclusion, hepatitis B virus (HBV) DNA ≥10⁴ /ml or hepatitis C virus (HCV) RNA≥103 /ml or higher); Chronic hepatitis B virus carriers who HBV DNA<2000 IU/ml(<104/ml), must receive anti-viral treatment throughout the study.
17. Participated in other clinical trials, or finish other clinical trials within 4 weeks.
18. Patients who may receive other anti-tumor systemic chemotherapy during the study.
19. Patients who has bone metastasis, have received Palliative radiotherapy (radiotherapy area > 5% marrow area).
20. Patients who may receive vaccination during the study, or previous had vaccination within 4 weeks.
21. Mental disorders history, or psychotropic drug abuse history.
22. Any other medical, psychiatric, or social condition deemed by the investigator to be likely to interfere with a subject's rights, safety, welfare, or ability to sign informed consent, cooperate, and participate in the study or would interfere with the interpretation of the results.