Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting children and young adults that is driven by a chimeric protein, DNAJ-PKAc. The development of molecular inhibitors of DNAJ-PKAc has been hampered by unacceptable on-target toxicity, but the chimera results in a tumor-specific antigen (neoantigen) that may be targeted immunologically. Here we conducted a phase 1 clinical trial of a therapeutic peptide vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC, who had not previously received immune checkpoint therapy. The primary objectives were safety and T cell responses after week 10 (priming phase). Of the 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. The median age was 24 years (range 12-47 years). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9 of 12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from which we identified multiple class-II-restricted T cell receptors with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in T cell receptor repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or human leukocyte antigen loss. Our findings demonstrate the potential for therapeutic vaccines targeting 'undruggable' oncogenic drivers and suggest a rubric for evaluating effective anti-neoantigen immunity. ClinicalTrials.gov identifier: NCT04248569 .
© 2025. The Author(s).