Bi-specific TCR-anti CD3 Redirected T-cell Targeting of NY-ESO-1- And LAGE-1-positive Tumors

Cancer Immunol Immunother. 2013 Apr;62(4):773-85. doi: 10.1007/s00262-012-1384-4. Epub 2012 Dec 22.

Abstract

NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157-165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1157-165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1157-165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacology
  • Antigens, Neoplasm / biosynthesis
  • Antigens, Neoplasm / immunology*
  • Antigens, Surface / biosynthesis
  • Antigens, Surface / immunology*
  • CD3 Complex / immunology
  • Cell Line, Tumor
  • Epitopes / immunology
  • Female
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunoglobulin Fragments / immunology
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism
  • Melanoma / immunology
  • Melanoma / metabolism
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism
  • Random Allocation
  • Receptors, Antigen, T-Cell / immunology*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacology*
  • T-Lymphocytes / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Bispecific
  • Antigens, Neoplasm
  • Antigens, Surface
  • CD3 Complex
  • CTAG1B protein, human
  • CTAG2 protein, human
  • Epitopes
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Immunoglobulin Fragments
  • Membrane Proteins
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins