Sequential personalized neoantigen vaccination following first-line treatments demonstrates safety and efficacy in advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has limited therapeutic options in the advanced stages; although first-line combinations of transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) and/or programmed cell death protein 1 (PD-1) inhibitors show promise, their efficacy is constrained by inadequate tumor-specific T-cell infiltration. To address this limitation, we conducted an investigator-initiated, single-center clinical trial (ChiCTR2300067818) evaluating the safety, feasibility, and preliminary efficacy of sequential personalized neoantigen vaccination following TACE plus TKI/PD-1-based therapy in patients with advanced HCC. Whole-exome and transcriptome sequencing identified patient-specific neoantigens, which were synthesized as long peptides and formulated with dual adjuvants for subcutaneous administration. Among 10 initially enrolled patients, 4 received personalized vaccination after comprehensive screening, with 2 patients (N03 and N04) completing the full 8-injection vaccination regimen. Sequential neoantigen vaccination demonstrated excellent safety profiles, with only mild injection-site reactions observed. Both patients achieved partial response following vaccination. Interferon-gamma Enzyme-Linked ImmunoSpot assays confirmed robust neoantigen-specific responses against multiple peptide pools in both patients. Dynamic monitoring revealed that serum alpha-fetoprotein and Des-gamma-carboxy prothrombin levels correlated with clinical responses, declining significantly during vaccination. These findings demonstrate that sequential personalized neoantigen vaccination following first-line TACE-based therapy is safe, feasible, and capable of inducing potent tumor-specific immune responses, supporting further investigation in larger clinical trials.