A peptide vaccine targeting the unique fusion protein that drives fibrolamellar liver cancer induced strong immune responses and kept one patient relapse-free for over 21 months after repeated prior treatment failures.
>21 months relapse-freeA patient with recurrent fibrolamellar HCC who had failed multiple prior treatments remained relapse-free for over 21 months after peptide vaccination
What the researchers found
DNAJB1-PRKACA fusion-derived peptides were confirmed as genuine HLA-presented neoantigens on tumor cells by mass spectrometry-based immunopeptidome analysis. These peptides induced both cytotoxic CD8+ T cells and T-helper 1 CD4+ T cells in preclinical testing. Single-cell RNA sequencing identified multiple T cell receptors specific for the fusion neoepitopes.
In a single-patient clinical application, vaccination with DNAJB1-PRKACA-derived peptides (combined with ongoing PARP inhibitor therapy) induced multifunctional CD4+ T cells with activated Th1 phenotype and high T cell receptor clonality. The vaccine-induced immune responses persisted over time and were accompanied by durable relapse-free survival of more than 21 months — in striking contrast to the patient's previous pattern of recurrent short-interval relapses under various treatments.
Why it matters
Fibrolamellar hepatocellular carcinoma has no approved targeted therapies and is often fatal. This study demonstrates that the cancer's driving mutation — present in virtually all cases — can be specifically targeted by peptide immunotherapy. Because nearly every patient carries the same fusion, this approach could become a standardized treatment rather than requiring individualized neoantigen identification, making it more practical than most personalized cancer vaccines.
How the study worked
Multi-stage study: (1) Identification of HLA class I and II neoantigen peptides from the DNAJB1-PRKACA fusion using mass spectrometry immunopeptidomics, (2) in vitro characterization of T cell responses to these peptides, (3) single-cell RNA sequencing of fusion-specific T cells to identify T cell receptors, and (4) clinical vaccination of one fibrolamellar HCC patient with the identified peptides alongside continued PARP inhibitor therapy, with longitudinal immune monitoring.
What this study cannot tell us
This is a single-patient clinical observation — the gold standard of evidence (randomized controlled trial) has not been met. The patient also received concurrent PARP inhibitor therapy, making it impossible to attribute the clinical benefit solely to the vaccine. The durability beyond 21 months and response in other patients are unknown. Mass spectrometry-based neoantigen identification requires specialized infrastructure not available at most centers.
How to read the evidence
This combines rigorous preclinical neoantigen characterization (mass spectrometry, T cell assays, single-cell sequencing) with a single-patient clinical observation. Published in Nature Communications, the preclinical work is strong, but the clinical evidence is limited to one patient with concurrent therapy.
When this study was published
Published in 2022, this study established the foundation for clinical development of DNAJB1-PRKACA-targeted peptide vaccines. Larger clinical trials may be underway or in planning stages.
The bigger picture
This study is a landmark in neoantigen-based cancer immunotherapy. Unlike most personalized cancer vaccines that target patient-specific mutations, fibrolamellar HCC's universal driver fusion creates a shared neoantigen targetable across all patients. This 'off-the-shelf' approach to neoantigen vaccination could serve as a model for other cancers driven by recurrent fusion events, such as Ewing sarcoma and certain leukemias.
Questions still open
- Will the durable response observed in this single patient be replicated in a larger clinical trial of fibrolamellar HCC patients?
- Can the vaccine's efficacy be separated from the concurrent PARP inhibitor therapy?
- Could this vaccination approach be applied prophylactically after surgical resection to prevent recurrence in fibrolamellar HCC?
Common questions
What makes fibrolamellar liver cancer unique from a treatment perspective?
How is this different from other cancer vaccines?
Read the original research
The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.
Nature communications, 13(1), 6401
Citation
Bauer, Jens; Köhler, Natalie; Maringer, Yacine; Bucher, Philip; Bilich, Tatjana; Zwick, Melissa; Dicks, Severin; Nelde, Annika; Dubbelaar, Marissa; Scheid, Jonas; Wacker, Marcel; Heitmann, Jonas S; Schroeder, Sarah; Rieth, Jonas; Denk, Monika; Richter, Marion; Klein, Reinhild; Bonzheim, Irina; Luibrand, Julia; Holzer, Ursula; Ebinger, Martin; Brecht, Ines B; Bitzer, Michael; Boerries, Melanie; Feucht, Judith; Salih, Helmut R; Rammensee, Hans-Georg; Hailfinger, Stephan; Walz, Juliane S. (2022). The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma.. Nature communications, 13(1), 6401. https://doi.org/10.1038/s41467-022-33746-3