CELL INTELLIGENCE · 肿瘤细胞治疗研究

BACKGROUND &amp; AIMS: There is strong rationale for integrated approaches combining immune checkpoint inhibitors with locoregional therapies in hepatocellular carcinoma (HCC). METHODS: The PEMRAD phase II trial investigated pembrolizumab in combination with stereotactic body radiation therapy (SBRT) in patients with advanced HCC following progression on sorafenib. Patients received pembrolizumab on Day 1, and SBRT commenced on Day 2. Up to 10 hepatic lesions (<20 cm) were treated with SBRT. Pembrolizumab was continued every 21 days until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate (ORR) by RECIST v1.1, with a hypothesized improvement to 40% for the combination. Tissue and liquid biopsies were collected for correlative analyses, including immunohistochemistry, longitudinal blood cytometry by time-of-flight, and serum cytokine assessment. RESULTS: Between March 2018 and March 2023, 18 of a planned 22 patients were enrolled; 11 (61%) had macrovascular invasion (MVI) and 15 (83%) had extrahepatic metastases. Viral hepatitis was the underlying etiology in 50%. The ORR was 41% (95% CI 18-67%). Median progression-free survival was 5.4 months (2.8-9.9) and median overall survival was 12.6 months (5.7-25.8). Of 34 liver lesions treated with SBRT, only three progressed, in two patients. Among the 11 patients with MVI, 5 (45%) achieved a response, including one complete response. Treatment-related adverse events of grade ≥3 occurred in four patients (22%). One treatment-related death due to myocarditis was observed. Peripheral immunophenotyping showed that higher abundance of CD8 + CD103 + T cells correlated with improved survival, whereas higher natural killer cell abundance was associated with inferior outcomes. CONCLUSION: The combination of SBRT and pembrolizumab demonstrated a high response rate as second-line therapy for advanced HCC and warrants further evaluation, particularly in patients with MVI. IMPACT AND IMPLICATIONS: This study demonstrates that combining stereotactic body radiotherapy with pembrolizumab is feasible and yields promising response rates in patients with advanced, previously treated hepatocellular carcinoma, including those with macrovascular invasion - a group typically associated with poor outcomes. These findings support further evaluation of this integrated approach and provide important guidance for the design of future clinical trials aimed at improving outcomes in advanced hepatocellular carcinoma.