A therapeutic vaccine for fibrolamellar hepatocellular carcinoma.

Abstract

2503 Background: 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. Methods: We conducted a phase 1 clinical trial of a therapeutic vaccine targeting DNAJ-PKAc (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC. The primary objectives were safety and T cell responses, defined as 2.5-fold increase of interferon gamma (IFN-γ)-producing DNAJB1-PRKACA chimera-specific T cells in the peripheral blood after week 10 (priming phase). The study was planned with 12 evaluable patients. FLC-Vac, consisting of a peptide encoding the DNAJB1-PRACA fusion plus poly-ICLC adjuvant, was administered on weeks 0, 1, 2, 3, 6, 9 during the priming phase of the study. Nivolumab, 3 mg/kg, followed by ipilimumab, 1 mg/kg, was administered every 3 weeks for 4 doses during the priming phase. After completion of the priming phase, FLC-Vac and nivolumab were continued in maintenance. Key exclusion criteria include age < 12 years and prior treatment with immune checkpoint inhibitors. The trial incorporated a safety lead-in portion in which the first 3 patients received vaccine monotherapy for 3 weeks prior to receiving combination therapy. Results: Among 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). Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ-PKAc-specific T cell responses were detected in 9/12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate (DCR) was 75% (9/12), with three partial responses (25%). All 3 responding patients are without evidence of active cancer after undergoing surgical debulking of residual disease. All patients with clinical responses also had DNAJ-PKAc-specific T cell responses, from whom we identified multiple class II-restricted T cell receptors (TCRs) with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in TCR repertoire features over time. In two patients who experienced eventual progression after initial clinical response, we found evidence that the loss of efficacy was likely due to T cell exhaustion, and in one case was restored with checkpoint rechallenge. Conclusions: Our findings demonstrate the potential for therapeutic vaccines targeting DNAJ-PKAc in FLC and suggest a rubric for evaluating effective anti-neoantigen immunity. Clinical trial information: NCT04248569 .