Tauroursodeoxycholic Acid Combined With PD-1/PD-L1 Immunotherapy in Advanced Hepatocellular Carcinoma: A Prospective Study

This prospective, randomized, controlled clinical trial investigates the efficacy and safety of combining tauroursodeoxycholic acid (TUDCA) with immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC).

Immunotherapy using PD-1 or PD-L1 inhibitors has become a cornerstone in treating advanced HCC. However, a significant proportion of patients exhibit limited response or develop resistance. One contributing factor may be the immunosuppressive liver tumor microenvironment, which impairs T cell activation and infiltration. TUDCA is a hydrophilic bile acid that exhibits cytoprotective and anti-inflammatory effects, and may enhance the immune response by improving liver immune homeostasis.

In this study, 300 patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC will be enrolled and randomly assigned to receive either PD-1/PD-L1 inhibitor monotherapy or combination therapy with TUDCA. The treatment cycle will last for 6 months, with a follow-up period of at least 6 months after treatment completion.

The primary outcome is objective response rate (ORR) as measured by RECIST 1.1 and mRECIST criteria. Secondary endpoints include progression-free survival (PFS), overall survival (OS), conversion to surgical eligibility, and biomarker dynamics.

Safety and tolerability will be closely monitored throughout the study. Dose-limiting toxicities, adverse events, and liver function parameters will be assessed regularly. The trial will also explore immune and inflammatory biomarkers associated with response to treatment.

This study aims to determine whether the addition of TUDCA can enhance the efficacy of ICIs in HCC and provide a novel treatment strategy for patients with advanced disease.

Inclusion criteria

Histologically or cytologically confirmed diagnosis of primary hepatocellular carcinoma (HCC).

Unresectable advanced HCC classified as Barcelona Clinic Liver Cancer (BCLC) stage C.

Age ≥ 18 years.

No prior systemic anti-tumor therapy for HCC before first dose of study treatment.

At least one measurable lesion according to RECIST v1.1, or a measurable lesion with clear progression after local treatment based on RECIST v1.1.

Adequate organ and bone marrow function within 7 days prior to enrollment, with no blood products, growth factors, albumin, or other intravenous/subcutaneous corrective treatment within 14 days prior to laboratory assessment:

Hematology:

Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelet count (PLT) ≥ 75 × 10⁹/L Hemoglobin (Hb) ≥ 9.0 g/dL

Liver function:

Total bilirubin (TBil) ≤ 2 × ULN ALT and AST ≤ 5 × ULN Serum albumin ≥ 28 g/L

Alkaline phosphatase (ALP) ≤ 5 × ULN

Renal function:

Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance (CCr) ≥ 50 mL/min (calculated by Cockcroft-Gault formula) Urinalysis shows urine protein < 2+; if urine protein ≥ 2+, 24-hour urine collection must show protein < 1g/24h

Coagulation:

International Normalized Ratio (INR) ≤ 2.3 or prothrombin time (PT) prolongation ≤ 6 seconds

Estimated life expectancy of ≥ 12 weeks.

Exclusion criteria

History of hepatic encephalopathy or liver transplantation.

Acute cholecystitis, acute cholangitis, patients with frequent biliary colic attacks, complete biliary obstruction, or gallbladder dysfunction (inability to contract and empty).

Patients with Child-Pugh class C or decompensated cirrhosis, including those with a history of severe hepatic encephalopathy or refractory ascites due to liver disease.

Patients with a previous diagnosis of biliary atresia without adequate biliary drainage (e.g., failed biliary-enteric anastomosis).

Pregnant or breastfeeding women.