Phase 1 trial of a therapeutic peptide vaccine for fibromellar hepatocellular carcinoma

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 that may be targeted immunologically. A phase 1 trial at Johns Hopkins University School of Medicine (Baltimore, MD) evaluated a 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 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for immunological and clinical endpoints. 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. In the subset of patients who completed the initial priming phase, the disease control rate was 75% (9/12), with three partial responses (25%). The authors conclude that these findings demonstrate the potential for therapeutic vaccines targeting ‘undruggable’ oncogenic drivers.