• Adult Men and women ≥ 18 years old

• Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.

• Patient should be able to comply with treatment, PK, and pharmacodynamic sample collection and willing to comply with study visits and procedures as per protocol.

• Patients must have pathological confirmation of HCC.

• Patient should be considered as non resectable by Multidisciplinary Team and liver surgeon, and non-eligible for liver transplantation (advanced HCC, BCLC C).

• Patient who progresses on, or is intolerant to, or has refused standard first line therapy and eligible for receiving IV infusion of Nivolumab and HIA administration of Ipilimumab

• Patient with active intrahepatic HCC. Part of the disease should not have undergone local treatments (including chemoembolization, or percutaneous targeted therapies).

• Patients with or without active viral infection (i.e., HCV, HBV) are eligible. Patients with active HBV/HCV are eligible provided they are adequately treated to control the disease.

• Patients should have measurable disease as defined by mRECIST criteria for response assessment.

⁃ ECOG status of 0 or 1 (Appendix 2).

⁃ Life expectancy of ≥ 12 weeks at the time of informed consent per Investigator assessment.

⁃ Adequate organ function as defined by the following:

∙ White blood cells (WBCs) ≥ 2000/mL

‣ Neutrophils ≥ 1000/mL

‣ Platelets ≥ 75 × 103/mL

‣ Hemoglobin ≥ 8.0 g/dL

‣ Creatinine \< 1.5 × ULN or creatinine clearance ≥ 40mL/min (Cockcroft-Gault formula)

‣ ALT and AST ≤ 3 × ULN or \< 5 x ULN in case of liver metastasis

‣ Lipase and amylase ≤ 1.5 × ULN

‣ Total bilirubin ≤ 1.5 × ULN

‣ Normal thyroid function, or stable on hormone supplementation per investigator assessment

⁃ Child-Pugh A, Without history of encephalopathy or clinically significant ascites

⁃ Women of childbearing potential (WOCBP) must have a negative urine or serum β-HCG pregnancy test within 14 days prior inclusion. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Sexually active female patients must agree to use two methods of effective contraception, one of them being a barrier method, or to abstain from sexual activity during the study and for at least 5 months after last study drug administration or must refrain from heterosexual activity during this same period.

⁃ Sexually active males patients must agree to use condom during the study and for at least 7 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration.

⁃ Patients shall be eligible to undergo pre-treatment and on-treatment tumor biopsies. Patients who either do not consent to a pre-treatment tumor biopsy or do not have accessible lesions will not be eligible.

⁃ Resolved acute effects of any prior therapy to baseline severity or NCI CTCAE v5 Grade ≤1 except for AEs not constituting a safety risk by investigator judgment.

⁃ Patients must be affiliated to a social security system or beneficiary of the same