The purpose of this study is to determine the safety and efficacy of immunotherapy toripalimab (anti-PD-1 mAb) combined with thermal ablation in patients with Hepatocellular Carcinoma (HCC).

1.1 Primary Objective & Hypothesis Determine the safety and efficacy of radiofrequency ablation (RFA)/microwave ablation (MWA) followed by toripalimab for advanced HCC by establishing the rates of toxicity that occur within 6 months after ablation. Hypothesis: Thermal ablation followed by toripalimab will have similar toxicity to toripalimab monotherapy. Thermal ablation enhances antitumor immune response and improves the best overall response rate compared to historical controls with toripalimab alone.

1.2 Secondary Objectives and Hypotheses Estimate the progression-free survival, and overall survival. Hypothesis: Disease control and survival will be better than that observed with toripalimab monotherapy.

1.3 Exploratory Objectives Explore changes in inflammatory biomarkers (including, but not limited to CD8+/Treg ratio, total CD4+ counts, total lymphocyte count) in pretreatment and on-treatment serially collected peripheral blood samples. Hypothesis: Changes in inflammatory biomarkers after thermal ablation may correlate with a more favorable response to immunotherapy.

Inclusion Criteria:

• With hepatocellular carcinoma, who meet the clinical diagnostic criteria of Primary HCC confirmed by histopathology, cannot undergo radical resection or radical ablation, and fail or intolerable to first-line systemic therapy
• Be willing and able to provide written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Have ECOG performance status 0-1.
• Pretreatment CT chest /abdomen /pelvis within 14 days of protocol enrollment.
• Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and biphenotypic tumors with a HCC component).
• Child Pugh Class A or B (score =7)
• Deemed ineligible for curative intent therapy with surgical resection or locoregional treatment or that had progression with at least 3 lesions thereafter.
• At least one lesion can be completely ablated by radiofrequency/microwave ablation.
• The the maximum diameter of a single lesion is less than 10 cm. Tumors account for less than 50% of the liver volume.
• Patients with extrahepatic disease are eligible.
• Progress or intolerance following at least one systemic treatment regimen.
• Have measurable disease based on RECIST 1.1.
• Demonstrate adequate organ function. Adequate Organ Function Laboratory Values System Laboratory Value Hematological Platelets ≥ 50,000 /mL Hepatic Serum total bilirubin ≤ 3 mg/dL AST (SGOT) and ALT (SGPT) ≤ 5 X ULN.
• Subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 150 days after the last dose of study therapy (for women of child-bearing potential) or 210 days after the last dose of study therapy (for men who have partners of child-bearing potential).
• Have a life expectancy of greater than 3 months (in the opinion of the treating physician).

Exclusion Criteria:

• Received local ablation or external beam radiation within 3 months .
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose of >10 mg prednisone daily or equivalent at time of first dose of trial treatment.
• Has a known history of active TB (Bacillus Tuberculosis).
• Has a known additional malignancy that is progressing or requires active treatment.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with allografts (including liver transplants) are not eligible for this protocol.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
• Has received a live vaccine within 30 days of planned start of study therapy.
• Prior anti-PD-1, anti-PD-L1, anti-PD-L2 or anti-CTLA4 immunotherapy.