Aurora kinase A-specific T-cell receptor gene transfer redirects T lymphocytes to display effective antileukemia reactivity

Blood. 2012 Jan 12;119(2):368-76. doi: 10.1182/blood-2011-06-360354. Epub 2011 Oct 24.

Abstract

Aurora kinase A (AURKA) is overexpressed in leukemias. Previously, we demonstrated that AURKA-specific CD8(+) T cells specifically and selectively lysed leukemia cells, indicating that AURKA is an excellent target for immunotherapy. In this study, we examined the feasibility of adoptive therapy using redirected T cells expressing an HLA-A*0201-restricted AURKA(207-215)-specific T-cell receptor (TCR). Retrovirally transduced T cells recognized relevant peptide-pulsed but not control target cells. Furthermore, TCR-redirected CD8(+) T cells lysed AURKA-overexpressing human leukemic cells in an HLA-A*0201-restricted manner, but did not kill HLA-A*0201(+) normal cells, including hematopoietic progenitors. In addition, AURKA(207-215)-specific TCR-transduced CD4(+) T cells displayed target-responsive Th1 cytokine production. Finally, AURKA(207-215)-specific TCR-transduced CD8(+) T cells displayed antileukemia efficacy in a xenograft mouse model. Collectively, these data demonstrate the feasibility of redirected T cell-based AURKA-specific immunotherapy for the treatment of human leukemia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aurora Kinase A
  • Aurora Kinases
  • Blotting, Western
  • Case-Control Studies
  • Feasibility Studies
  • Flow Cytometry
  • Genes, T-Cell Receptor / genetics*
  • Genetic Therapy*
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunotherapy*
  • Leukemia / genetics
  • Leukemia / immunology
  • Leukemia / therapy*
  • Luciferases / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / immunology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Interleukin-2 / physiology
  • T-Cell Antigen Receptor Specificity
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transduction, Genetic
  • Tumor Cells, Cultured

Substances

  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • RNA, Messenger
  • Receptors, Interleukin-2
  • Luciferases
  • AURKA protein, human
  • Aurka protein, mouse
  • Aurora Kinase A
  • Aurora Kinases
  • Protein Serine-Threonine Kinases