Sequential TACE and SBRT Followed by ImmunoTherapy for Downstaging HCC for Hepatectomy

Inclusion Criteria:

1. Diagnosis of HCC confirmed pathologically or made according to American Association for the Study of Liver Diseases (AASLD) practice guideline 2010: patients with cirrhosis of any etiology and patients with chronic hepatitis B (HBV) who may not have fully developed cirrhosis, the presence of liver nodule \>1cm and demonstrated in a single contrast-enhanced dynamic imaging \[magnetic resonance imaging (MRI)\] of intense arterial uptake and "washout" in portal venous and delayed phases.
2. Male or female subjects with age: 18-75 years old
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
4. Tumor size 5-15cm or number of lesions ≤3 or segmental portal vein involvement
5. Child-Pugh liver function class A-B7
6. Liver volume minus intrahepatic GTV \>700 cc.
7. Minimal distance from GTV to stomach, duodenum, small or large bowel \>1 cm.
8. No prior systemic therapy nor immunotherapy
9. No prior trans-arterial chemo-embolization (TACE)
10. No prior radiotherapy to the liver or selective internal radiation (SIRT)
11. Written informed consent obtained for clinical trial participation and providing archival tumor tissue, if available.
12. Subjects with confirmed concomitant HBV infection (defined as HBsAg positive or HBV DNA detectable) that are eligible for inclusion must be treated with antiviral therapy (per local institutional practice) prior to enrollment to ensure adequate viral suppression (HBV DNA \<2000 IU/mL), must remain on antiviral therapy for the study duration, and continue therapy for 6 months after the last dose of investigational product(s)
13. At least one measurable lesion according to RECIST v1.1.
14. Adequate organ and marrow function, as defined below:

    * Hemoglobin ≥9 g/dL
    * Absolute neutrophil count ≥1,500/μL
    * Platelet count ≥100,000/μL
    * Total bilirubin ≤2.0 × ULN
    * ALT ≤3 × ULN
    * Albumin ≥2.8 g/dL
    * INR ≤1.6
    * Calculated creatinine clearance ≥45 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance
15. Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception
16. Females of childbearing potential must have negative serum or urine pregnancy test

Exclusion Criteria:

1. Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured
2. Contraindicated of SBRT: Any one hepatocellular carcinoma \>15 cm; Total maximal sum of hepatocellular carcinoma \>20 cm; More than 3 discrete hepatic nodule; Direct tumor extension into the stomach, duodenum, small bowel, large bowel, common or main branch of biliary tree
3. Severe, active co-morbidity
4. Presence of extra-hepatic metastases (M1)
5. Left portal vein, right portal vein, main portal vein or inferior vena cava (IVC) thrombosis or involvement
6. Presence of clinically meaningful ascites as ascites requiring non pharmacologic intervention (eg, paracentesis) or escalation in pharmacologic intervention to maintain symptomatic control
7. Hepatic encephalopathy
8. Active or untreated gastrointestinal varices
9. Untreated central nervous system (CNS) metastatic disease, lepto-meningeal disease, or cord compression
10. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke ( \<6 months prior to enrollment), myocardial infarction ( \<6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
11. Prior treatment with any immune checkpoint inhibitors or an antibody targeting immuno-regulatory receptors or mechanisms
12. Irritable bowel syndrome or other serious gastrointestinal chronic conditions associated with diarrhea within the past 3 years prior to the start of treatment
13. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
14. On chronic systemic steroid or any other forms of immunosuppressive medication within 14 days prior to the treatment. Except:

    1. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
    2. Systemic corticosteroids at physiologic doses \<=10 mg/day of prednisone or equivalent;
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
15. Active or prior documented autoimmune or inflammatory disorders in the past 2 years, except diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment
16. History of primary immunodeficiency or solid organ transplantation
17. Receipt of live, attenuated vaccine within 28 days prior to the study treatment
18. Active infection requiring systemic therapy
19. Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
20. Females who are pregnant, lactating, or intend to become pregnant during their participation in the study
21. Psychiatric disorders and substance (drug/alcohol) abuse