Gene therapy of patient-derived T lymphocytes to target and eradicate colorectal hepatic metastases

Dis Colon Rectum. 2003 Jun;46(6):793-804. doi: 10.1007/s10350-004-6659-1.


Purpose: The overall aim of this study was to develop a novel treatment for colorectal cancer based on the use of gene therapy. Genetic modification of T lymphocytes has been used to specifically target and kill tumor cell lines directly. To test the efficacy of this method with clinically relevant materials, this study investigated the potential of T lymphocytes derived from patients with advanced colorectal disease to target autologous primary tumor material. METHODS T lymphocytes isolated preoperatively were modified genetically with recombinant retroviruses encoding CD3zeta-based chimeric immune receptors and were tested for functional activity against freshly isolated autologous tumor cells harvested from hepatic colorectal metastases.

Results: Patient-derived T cells were successfully transduced, and chimeric immune receptor expression was confirmed. Carcinoembryonic antigen expression on freshly isolated colorectal tumor cells was also demonstrated by molecular and immunohistochemical techniques. T cells expressing the anticarcinoembryonic antigen receptor were specifically activated by coculture with disaggregated or intact, diced tumor, whereas control non-carcinoembryonic antigen-targeted T-cell populations failed to activate.

Conclusions: These results indicate that gene-targeted primary T lymphocytes depict specific functional activity against autologous colorectal tumor cells. This evidence indicates that chimeric immune receptor-expressing T cells may be able to circumvent the mechanisms used by tumor cells to avoid immune cell activity in vivo. This study emphasizes the potential of this approach as a therapy for carcinoembryonic antigen-expressing primary colorectal tumor and its metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoembryonic Antigen / analysis
  • Coculture Techniques
  • Colorectal Neoplasms / pathology*
  • Gene Targeting*
  • Gene Transfer Techniques
  • Genetic Therapy*
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / immunology
  • Liver Neoplasms / secondary*
  • Liver Neoplasms / therapy*
  • Lymphocyte Activation
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Fusion Proteins / immunology
  • Retroviridae / genetics
  • T-Lymphocytes*
  • Transduction, Genetic
  • Tumor Cells, Cultured


  • Carcinoembryonic Antigen
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins