Zhu et al. used a lentivector and peptide prime/boost immunization in human HLA-A2 transgenic mice to identify CD8+ T cells and corresponding TCR genes that recognize the hepatocellular carcinoma (HCC)-associated antigen α-fetoprotein (AFP). Human T cells engineered to express the murine AFP-specific TCRs showed potent and specific cytotoxicity against HLA-A2+AFP+ HepG2 HCC tumor cells in vitro. Adoptive transfer of the engineered cells into immunodeficient mice efficiently prevented/eradicated large, established HepG2 HCC tumors.
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 alpha-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. This article is protected by copyright. All rights reserved.
Author Info: (1) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (2) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, G
Author Info: (1) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (2) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (3) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (4) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (5) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (6) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (7) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (8) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (9) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (10) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (11) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (12) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. Department of Surgery, Medical College of Georgia, Augusta University, Augusta, GA, 30912. (13) Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA, 30912. Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, 30912.
