Engineering alpha-fetoprotein to develop vaccines and T cell immunotherapies for hepatocellular carcinoma: From preclinical studies to future perspectives

AFP has been serving as a biomarker for the diagnosis of HCC for many years. Now, research has been conducted to use it as an immunological target for HCC immunotherapy. However, because of the self-nature of AFP, the immune activation and antitumor effects of the current AFP-based vaccines are weak. T cell epitope engineering was employed to create immunogenic AFP. A proof of principle was obtained in an animal model, demonstrating that the epitope-engineered-AFP gene vaccine indeed potently activated AFP-specific CD8 T cells, which critically could cross-recognize native-AFP peptides and kill AFP+ tumor cells. Importantly, immunization with engineered AFP increased liver infiltration of AFP-specific CD8 T cells and prevented the carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with engineered AFP gene vaccine generated CD8 memory cells that could detect and respond to evolving HCC tumor cells, enhancing the prevention of autochthonous HCC. This study provides a blueprint for us to develop effective human AFP-based HCC vaccines that may be used to prevent HCC relapse after liver resection and de novo tumor development in high-risk populations. In addition, the new AFP-based HCC vaccines may allow us to identify high-quality TCR genes for engineering human T cells for adoptive immunotherapy of HCC as our effort.