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

Hepatology. 2018 Aug;68(2):574-589. doi: 10.1002/hep.29844. Epub 2018 Jun 12.

Abstract

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T-cell receptors (TCRs) 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, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (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 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (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 five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA-A2/AFP158 tetramer. TCR gene-engineered human T (TCR-T) cells 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 TCR-T cells could eradicate HepG2 tumors in NSG mice.

Conclusion: We have identified 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. (Hepatology 2018).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Hepatocellular / immunology*
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • HLA-A2 Antigen / immunology
  • Hep G2 Cells
  • Humans
  • Immunotherapy / methods*
  • Liver Neoplasms / immunology*
  • Mice
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / immunology
  • alpha-Fetoproteins / immunology*

Substances

  • HLA-A2 Antigen
  • Receptors, Antigen, T-Cell
  • alpha-Fetoproteins