Abstract A030: Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCR) specific for HCC-associated antigens, such as α-fetoprotein (AFP), can potentially redirect human T-cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, by using lentivector and peptide immunization, we identified a population of CD8-T-cells in HLA-A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158-specific mouse CD8-T-cells eradicated HepG2 tumor xenografts as large as 2cm in diameter in immunocompromised NSG mice. We then established T-cell hybridoma clones from the AFP158-specific mouse CD8-T-cells and identified three sets of paired TCR genes out of 5 hybridomas. Expression of the murine TCR genes redirected primary human T-cells to bind HLA-A2/AFP158 tetramer. The TCR gene-engineered human T-cells (TCR-T) also specifically recognized HLA-A2+AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR-T-cells could specifically kill HLA-A2+AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific human TCR-T-cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified novel AFP-specific murine TCR genes that can redirect human T-cells to specifically recognize and kill HCC tumor cells, and those AFP158-specific TCRs have a great potential to engineer a patient’s autologous T-cells to treat HCC tumors. Citation Format: Yukai He, Wei Zhu, Yibing Peng, Lan Wang, Yuan Hong, Juan Wu, Esteban Celis. Identification of α-fetoprotein-specific T-cell receptors for hepatocellular carcinoma immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A030.