FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion.
Authors: Heitmann Jonas S. , Bitzer Michael , Hackenbruch Christopher , Bauer Jens , Maringer Yacine , Nelde Annika , Salih Helmut R. , Walz Juliane S. 
Published: July 2024

TPS2702 Background: The DNAJB1-PRKACA fusion transcript is the driving force behind tumor development in fibrolamellar hepatocellular carcinoma (FL-HCC) and other tumor types, such as oncocytic neoplasms of the pancreas and bile ducts. Consequently, it serves as a versatile target for innovative cancer therapies. Recently, the DNAJB1-PRKACA fusion protein was recognized as a source of HLA-presented neoepitopes targetable by to T cell-based immunotherapy (1). The FusionVAC-22 neoepitope, derived from DNAJB1-PRKACA fusion, is computationally predicted to bind to 1,290 different HLA class II alleles. Furthermore, it includes embedded HLA class I ligands for 13 out of the 20 most common HLA class I alleles, covering 93.8% of the global population This broad coverage enables the widespread application of FusionVAC-22-based immunotherapies. The initial use of FusionVAC-22-based peptide vaccines, adjuvanted with the TLR1/2 agonist XS15 emulsified in Montanide ISA 51 VG, in two FL-HCC patients was well-tolerated and demonstrated the induction of robust and long-lasting T cell responses. Notably, T cell responses coincided with 32 months and 13 months of progression-free survival for the respective patients. Methods: Building on these promising outcomes, we have initiated a Phase I open-label, multicentric clinical trial to assess the immunogenicity, safety, toxicity, and initial signs of efficacy of the FusionVAC-22-based peptide vaccine combined with the immune checkpoint inhibitor (ICI) atezolizumab. The trial includes 20 patients with locally advanced or metastatic FL-HCC or other malignancies carrying the DNAJB1-PRKACA fusion transcript without available standard therapy. Key eligibility criteria involve the absence of autoimmune phenomena due to prior immunotherapy agents (≥ grade 3) and no history of tissue or organ allografts. The FusionVAC-22-based peptide vaccine is administered twice with a 4-week interval, with an option for a booster vaccination after 11 months. ICI administration begins on day 15 after the first vaccination and continues every 4 weeks for 1 year, followed by a 6-month follow-up. Primary trial objectives include assessing immunogenicity in terms of peptide-specific T cell responses up to 28 days after the second vaccination, as well as evaluating the safety and toxicity of the peptide vaccine in combination with ICI. Safety assessment is based on the frequency of adverse events according to CTCAE v5.0. Clinical efficacy is determined through iRECIST assessment on imaging. Additionally, disease control rate, quality of life, and overall and progression-free survival will be evaluated. So far, 3 out of 20 planned patients have been enrolled. 1. Bauer et al., Nat. Commun, 2022. Clinical trial information: NCT05937295 .